Carboxamides as ubiquitin-specific protease inhibitors

ABSTRACT

The present disclosure relates to modulators, such as inhibitors, of at least one pathway chosen from USP28 and USP25, pharmaceutical compositions comprising the inhibitors, and methods of using the inhibitors. The modulators, such as inhibitors, of at least one pathway chosen from USP28 and USP25 can be useful in the treatment of cancers, among other ailments.

TECHNICAL FIELD

The present disclosure is directed to modulators of at least one pathway chosen from ubiquitin-specific protease 28 (USP28) and/or ubiquitin-specific protease 25 (USP25) useful in the treatment of diseases or disorders associated with at least one pathway chosen from USP28 and USP25 enzymes. Specifically, the disclosure is concerned with chemical entities and compositions inhibiting at least one pathway chosen from USP28 and USP25, methods of treating diseases or disorders associated with at least one pathway chosen from USP28 and USP25, and methods of synthesis of these compounds.

BACKGROUND

USP28 and USP25 are cysteine isopeptidases of the USP sub-family of DUBs containing three distinct domains: an N-terminal UBA-like domain; a pair of ubiquitin-interacting motifs (UIM) and a USP domain that is predicted to have the conserved fold of the USP sub-family (Nijman et al., Cell 2005, 123, 773-786; Komander et al., Mol. Cell Bio. 2009, 10, 550-563). USP28 and USP25 exert their function through regulating the stability of a plethora of cellular proteins. USP28 has been characterized as a tumor-promoting factor and has been found to stabilize many oncoproteins. USP25 has been characterized as a tumor-promoting factor and as a regulator of cellular responses related to autoimmune disease, inflammation, and infectious diseases (such as viruses and bacteria).

Amplification, deletions and mutations of USP28 have been identified in multiple cancer types, including breast cancer, AML, ovarian cancer, and colorectal cancer. (cbioportal; http://www.cbioportal.org; Diefenbacher et al., J. of Clin. Investi. 2014, 124, 3407-3418; Popov et al., Nat. Cell. Biol. 2007, 9, 729-731). Furthermore, USP28 overexpression has been correlated with poor prognosis in patients with glioblastoma, non-small cell lung carcinoma and bladder cancers suggesting that USP28 plays an important role in tumorigenesis of these tumor types. (Wang et al. Exp. Biol. Med. 2016, 255-264; Zhang et al. J. Cell. Mol. Med. 2015, 19, 799-805; Guo et al., Tumor Bio. 2014, 35, 4017-4022).

A large-scale shRNA screen has also identified a role of USP28 in the control of the stability of MYC protein. (Popov, Nat. Cell. Biol., 765-774). MYC is a master regulator of the transcription of genes involved in cell growth, proliferation and apoptosis and is essential for tumor initiation and maintenance in many tumor types. (Meyer et al., Nat. Rev. Cancer 2008, 8, 976-990; Conacci-Sorrell et al., Cold Spring Harb. Perspect. Med. 2014, 4, 1-24; Huang et al., Cold Spring Harb. Perspect. Med. 2013; Roussel et al., Cold Spring Harb. Perspect. Med. 2013; Gabay et al., Cold Spring Harb. Perspect. Med. 2014; Schmitz et al., Cold Spring Harb. Perspect. Med. 2014). In addition, MYC is the most frequently amplified oncogene in human cancer, with alterations in many tumor types including breast, lung and prostate. (Beroukhim et al., Nature 2010, 463, 899-905). Knockdown of the USP28 gene has been shown to lead to a decrease of MYC protein and an associated inhibition of growth in a panel of human cancer cell lines in vitro. (Popov, Nat. Cell Biol., 765-774).

USP28 has also been reported to be required to impart stability on the LSD1 (lysine-specific demethylase 1) protein. (Wu et al., Cell Rep. 2013, 5, 224-236). LSD1 is a histone demethylase that complexes with many partner proteins to control cellular pluripotency and differentiation. (Metzger et al. Nature 2005, 437, 436-439; Toffolo et al, J. Neurochem. 2014 128, 603-616, 2014; Periz et al., PloS Biology 2015). Knockdown of USP28 in tumor cells has been shown to lead to the destabilization of LSD1 protein, the suppression of cancer stem cell (CSC)-like characteristics in vitro, and the inhibition of tumor growth in vivo. (Wu, Cell Rep., 224-236). Small molecule inhibitors of LSD1 have shown antitumor activity in models of AML and Ewing sarcoma. (Sankar et al., “Reversible LSD1 inhibition interferes with global EWS/ETS transcriptional activity and impedes Ewing sarcoma tumor growth” Clin Cancer Res. 2014 4584-4597; Schenk et al., Nat. Med. 2012, 18, 605-611). Thus, USP28 inhibition represents an alternate approach to targeting LSD1 in these tumor types.

USP28 inhibition has also been shown to reduce NICD1-Levels and to lead to inhibition of the NOTCH pathway activity. (Diefenbacher et al.). NOTCH signaling controls diverse cellular differentiation decisions and drives tumorigenesis in certain tumor types. NOTCH1 is a potent T-cell oncogene, with >50% of T-cell acute lymphoblastic leukemia (T-ALL) cases carrying activating mutations in NOTCH1. (Weng et al. Science 2004, 306, 269-271). Increased NOTCH1 protein levels have also been associated with disease progression in colon cancer. (Meng et al., Cancer Res. 2009, 69, 573-582). NOTCH1 rearrangements lead to constitutive pathway activation and drive tumorigenesis in many cancer types, including triple-negative breast cancer. (Stoeck et al., Cancer Discov. 2014, 4, 1154-1167).

Other reported substrates of USP28 include c-Jun, Cyclin E, HIF-1α, Claspin, 53BP1, and Mdc1, many of which play important roles in tumorigenesis in humans. (Diefenbacher et al.; Flügel et al. Blood 2012, 119, 1292-1301; Zhang et al., “A role for the deubiquitinating enzyme USP28 in control of the DNA-damage response” Cell 2006, 126, 529-542). Interestingly, many USP28 substrates are recognized by FBW7, the substrate recognition subunit of SCF (FBW7) E3 ubiquitin ligase. (Diefenbacher et al.). FBW7 recognizes USP28 substrates in a phosphorylation-dependent manner and targets them for ubiquitination ultimately leading to their proteasomal degradation. The antagonizing roles of USP28 and FBW7 on their shared oncoprotein substrates indicate the intricate nature of protein stability control and may provide additional therapeutic opportunities for cancer treatment.

Mice with a germline knockout of USP28 have been shown to be viable and fertile, confirming that USP28 activity is not required for normal development and reproductive function. (Knobel et al., Molecular and Cellular Biology 2014, 34, 2062-2074). Conditional knockout of USP28 in mouse intestine led to the reduction of oncoproteins including c-Myc, active NOTCH (NICD1) and c-JUN which was associated with decreased intestinal cell proliferation and enhanced differentiation. More importantly, intestinal tumorigenesis induced by APC mutation was effectively blocked with acute USP28 depletion suggesting that USP28 could be an appealing target to reduce tumor burden and improve survival for intestinal cancers. (Diefenbacher et al.).

In summary, USP28 and USP25 play important roles in promoting tumorigenesis in cells and modulating immune responses. Its major role being in the deubiquitination and stabilization of diverse oncoproteins and epigenetic drivers and immunomodulatory proteins among other cellular factors, which are necessary for immune responses and tumor initiation and growth in humans. Inhibition of USP28 and/or USP25 with small molecule inhibitors therefore can be developed for medical use, such as for the treatment for cancer such as lung cancer. For this reason, there remains a considerable need for novel and potent small molecule inhibitors of USP28 and/or USP25.

SUMMARY

The present disclosure relates to chemical entities chosen from compounds of Formula (I)

and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof, wherein:

-   -   X is chosen from C(R)₂ and O;     -   Y is chosen from C and N;     -   R is chosen from H, halogens, C₁-C₆ alkyl, —OH, and —CN, wherein         any R group containing hydrogen can have one or more hydrogen         replaced with deuterium;     -   R₁ is chosen from 6-12 membered heteroaryls optionally         substituted with one or more substituent chosen from R₅ and R₆,         wherein a 6-membered nonfused heteroaryl is substituted with one         or more R₆, and further wherein any R₁ group containing hydrogen         can have one or more hydrogen replaced with deuterium;     -   R₂ is chosen from N-linked and C-linked 4-12 membered         heterocyclyls, and an O linked to a heterocyclyl, wherein the         heterocyclyls are optionally substituted with one or more R₅, a         sulfur member of the heterocyclyls can be S(O) or S(O)2, and         further wherein any R₂ group containing hydrogen can have one or         more hydrogen replaced with deuterium;     -   R₃ is independently chosen from H, (C₁-C₆) alkyl, (C₁-C₆)         alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH,         —CN, (C₃-C₈) cycloalkyl, heterocycloalkyl, aryl, and heteroaryl         groups, wherein alkyls are optionally substituted with one or         more substituent independently chosen from (C₁-C₆) alkoxy and         —OH, and wherein the cycloalkyl, heterocycloalkyl, aryl, and         heteroaryl groups are optionally substituted with one or more         R₇;     -   R₄ is chosen from H, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)         haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —CN, (C₃-C₈)         cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups,         wherein alkyls are optionally substituted with one or more         substituent independently chosen from (C₁-C₆) alkoxy and —OH,         and wherein the cycloalkyl, heterocycloalkyl, aryl, and         heteroaryl groups are optionally substituted with one or more         R₅, and further wherein any R₄ group containing hydrogen can         have one or more hydrogen replaced with deuterium;

R₅ is independently chosen from —OH, —NH₂, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, cycloalkyl, heterocycloalkyl, and —C(O)-heterocycloalkyl groups, wherein alkyls are optionally substituted with one or more substituent independently chosen from (C₁-C₆) alkoxy and —OH, and wherein any R₅ group containing hydrogen can have one or more hydrogen replaced with deuterium;

-   -   R₆ is chosen from —N(C₁-C₆)alkyl-aryls,         —N(C₁-C₆)alkyl-heteroaryls, and —N(C₁-C₆)alkyl-heterocyclyl         groups, wherein the groups are optionally substituted with one         or more substituent chosen from —OH, —NH, halogens, (C₁-C₆)         alkyl, (C₁-C₆) alkoxy, and (C₁-C₆) haloalkyl groups, and further         wherein any R₆ group containing hydrogen can have one or more         hydrogen replaced with deuterium;     -   R₇ is independently chosen from —OH, —NH₂, (C₁-C₆) alkyl,         (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen,         cycloalkyl, heterocycloalkyl, and —C(O)-heterocycloalkyl groups,         wherein alkyls are optionally substituted with one or more         substituent independently chosen from (C₁-C₆) alkoxy and —OH;         and     -   n is 0, 1, 2, or 3.

The compound of Formula (I) can be a compound, or pharmaceutically acceptable salt thereof, wherein:

-   -   X is chosen from C(R)₂ (e.g., C(R)(R) where each R is the same         or different) and O;     -   Y is chosen from C (e.g., CH or C(R) where R is the same or         different from R in moiety X) and N;     -   R is independently chosen from H, halogens, C₁-C₆ alkyl, —OH,         and —CN;     -   R₁ is chosen from 6-12 membered heteroaryls optionally         substituted with one or more substituent chosen from R₅ and R₆,         wherein a 6-membered nonfused heteroaryl is substituted with one         or more R₆;     -   R₂ is chosen from N-linked 4-12 membered heterocyclyls, C-linked         4-12 membered heterocyclyls, and O-linker to a heterocyclyl,         wherein the N-linked, C-linked or O-linker heterocyclyls are         optionally substituted with one or more R₅;     -   R₃ is independently chosen from H, (C₁-C₆) alkyl, (C₁-C₆)         alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH,         —CN, (C₃-C₈) cycloalkyl, heterocycloalkyl, aryl, and heteroaryl         groups, wherein alkyls are optionally substituted with one or         more substituent independently chosen from (C₁-C₆) alkoxy and         —OH, and wherein the cycloalkyl, heterocycloalkyl, aryl, and         heteroaryl groups are optionally substituted with one or more         R₇;     -   R₄ is chosen from H, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)         haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —CN, (C₃-C₈)         cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups,         wherein alkyls are optionally substituted with one or more         substituent independently chosen from (C₁-C₆) alkoxy and —OH,         and wherein the cycloalkyl, heterocycloalkyl, aryl, and         heteroaryl groups are optionally substituted with one or more         R₅;     -   R₅ is independently chosen from —OH, —NH₂, (C₁-C₆) alkyl,         (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen,         cycloalkyl, heterocycloalkyl, and —C(O)-heterocycloalkyl groups,         wherein alkyls are optionally substituted with one or more         substituent independently chosen from (C₁-C₆) alkoxy and —OH;     -   R₆ is chosen from —N—(C₁-C₆)alkyl-aryls,         —N—(C₁-C₆)alkyl-heteroaryls, and —N—(C₁-C₆)alkyl-heterocyclyl         groups, wherein the groups are optionally substituted with one         or more substituent chosen from —OH, —NH, halogens, (C₁-C₆)         alkyl, (C₁-C₆) alkoxy, and (C₁-C₆) haloalkyl groups;     -   R₇ is independently chosen from —OH, —NH₂, (C₁-C₆) alkyl,         (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen,         cycloalkyl, heterocycloalkyl, and —C(O)-heterocycloalkyl groups,         wherein alkyls are optionally substituted with one or more         substituent independently chosen from (C₁-C₆) alkoxy and —OH;         and     -   n is 0, 1, 2, or 3.

In other examples, the compound of Formula (I) can be a compound, or pharmaceutically acceptable salt thereof, wherein:

-   -   X is chosen from C(R)₂ (e.g., C(R)(R) where each R is the same         or different) and O;     -   Y is chosen from C (e.g., CH or C(R) where R is the same or         different from R in moiety X) and N;     -   each R in X and Y is independently chosen from H, halogens,         C₁-C₆ alkyl, —OH, and —CN;     -   R₁ is chosen from heteroaryls optionally substituted with one or         more substituent chosen from R₅ and R₆, wherein the heteroaryl         is optionally substituted with one or more R₆;     -   R₂ is chosen from N-linked-heterocyclyls,         C-linked-heterocyclyls, and O-linker-heterocyclyls, wherein the         N-linked, C-linked or O-linker heterocyclyls are optionally         substituted with one or more R₅;     -   each R₃ is independently chosen from H, (C₁-C₆) alkyl, (C₁-C₆)         alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH,         —CN, (C₃-C₈) cycloalkyl, heterocycloalkyl, aryl, and heteroaryl         groups, wherein the alkyls are each optionally substituted with         one or more substituent independently chosen from (C₁-C₆) alkoxy         and —OH, and wherein the cycloalkyl, heterocycloalkyl, aryl, and         heteroaryl groups are optionally substituted with one or more         R₇;     -   each R₄ is independently chosen from H, (C₁-C₆) alkyl, (C₁-C₆)         alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH,         —CN, (C₃-C₈) cycloalkyl, heterocycloalkyl, aryl, and heteroaryl         groups, wherein alkyls are each optionally substituted with one         or more substituent independently chosen from (C₁-C₆) alkoxy and         —OH, and wherein the cycloalkyl, heterocycloalkyl, aryl, and         heteroaryl groups are optionally substituted with one or more         R₅;     -   each R₅ is independently chosen from —OH, —NH₂, (C₁-C₆) alkyl,         (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen,         cycloalkyl, heterocycloalkyl, and —C(O)-heterocycloalkyl groups,         wherein the alkyls are each optionally substituted with one or         more substituent independently chosen from (C₁-C₆) alkoxy and         —OH;     -   each R₆ is independently chosen from amino-alkyl-aryls (e.g.,         —N—(C₁-C₆)alkyl-aryls), amino-alkyl-heteroaryls (e.g.,         —N—(C₁-C₆)alkyl-heteroaryls), amino-alkyl-cyclyl and         amino-alkyl-heterocyclyl (e.g., —N—(C₁-C₆)alkyl-heterocyclyls)         groups, wherein these groups are optionally substituted with one         or more substituent chosen from —OH, —NH, halogens, (C₁-C₆)         alkyl, (C₁-C₆) alkoxy, and (C₁-C₆) haloalkyl groups;     -   each R₇ is independently chosen from —OH, —NH₂, (C₁-C₆) alkyl,         (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen,         cycloalkyl, heterocycloalkyl, and —C(O)-heterocycloalkyl groups,         wherein the alkyls are each optionally substituted with one or         more substituent independently chosen from (C₁-C₆) alkoxy and         —OH; and     -   n is 0, 1, 2, or 3.

Another aspect of the present disclosure relates to a method of treating a disease or disorder associated with inhibition of USP28. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with inhibition of USP28 an effective amount of at least one chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof.

Another aspect of the disclosure relates to a method of treating a disease or disorder associated with inhibition of USP25. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with inhibition of USP25 an effective amount of a at least one chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof.

Another aspect of the disclosure relates to a method of treating a disease or disorder associated with inhibition of at least one pathway chosen from USP28 and USP25. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with inhibition of at least one pathway chosen from USP28 and USP25 effective amount of at least one chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof.

Another aspect of the disclosure is directed to a method of inhibiting USP28. The method involves administering to a patient in need thereof an effective amount of at least one chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.

Another aspect of the disclosure is directed to a method of inhibiting USP25. The method involves administering to a patient in need thereof an effective amount of at least one chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.

Another aspect of the disclosure is directed to a method of inhibiting at least one pathway chosen from USP28 and USP25. The method involves administering to a patient in need thereof an effective amount of at least one chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof.

Another aspect of the disclosure relates to a method of treating cancer. The method comprises administering to a patient in need thereof an effective amount of at least one chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof.

Another aspect of the disclosure is directed to pharmaceutical compositions comprising at least one chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof, and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

Another aspect of the present disclosure relates to at least one chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof, for use in the manufacture of a medicament for treating a disease associated with inhibiting USP28.

Another aspect of the present disclosure relates to the use of at least one chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof, in the treatment of a disease associated with inhibiting USP28.

Another aspect of the present disclosure relates to the use of at least one chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof, in the treatment of a disease associated with inhibiting USP25.

Another aspect of the present disclosure relates to the use of at least one chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof, in the treatment of a disease associated with inhibiting at least one pathway chosen from USP28 and USP25.

DESCRIPTION OF THE EMBODIMENTS

Compounds useful for inhibiting USP 28 and/or USP25 are disclosed herein, including USP25 Inhibitor compounds, USP28 Inhibitor compounds and USP28/25 Inhibitor compounds as defined herein. The USP28/25 Inhibitor, USP28 Inhibitor and/or USP25 Inhibitor compounds can be a compound disclosed herein, including a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of Formula (IV), a compound of Formula (V), a compound of Formula (VI), and/or a compound of Formula (VII).

The term “USP28 Inhibitor” compound as used herein refers to a compound disclosed herein (e.g., a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of Formula (IV), a compound of Formula (V), a compound of Formula (VI), and/or a compound of Formula (VII)) having an IC₅₀ of 2 micromolar or less in the Ubiquitin-Rhodamine 110 Assay for USP28 as described in Example A-1(a) and/or the Ubiquitin-Rhodamine 110 Assay for USP28 as described in Example A-1(b) herein. For example, the USP28 Inhibitor can be a compound of a formula disclosed herein having an IC₅₀ value of up to 2 micromolar using the Ubiquitin-Rhodamine 110 Assay for USP28 as described in Example A-1(a), including IC₅₀ values ranging from 0.001-2 micromolar, preferably 0.001-0.2 micromolar, and more preferably 0.001-0.05 micromolar. The USP28 Inhibitor can be a compound of a formula disclosed herein having an IC₅₀ value of up to 2 micromolar using the Ubiquitin-Rhodamine 110 Assay for USP28 as described in Example A-1(b), including IC₅₀ values ranging from 0.001-2 micromolar, preferably 0.001-0.2 micromolar, more preferably from 0.001-0.05 micromolar. The USP28 Inhibitor can be a compound of a formula disclosed herein having an IC₅₀ values of up to 2 micromolar using both the Ubiquitin-Rhodamine 110 Assay for USP28 as described in Example A-1(a) and the Ubiquitin-Rhodamine 110 Assay for USP28 as described in Example A-1(b), including IC₅₀ values of 0.001-2 micromolar, preferably 0.001-0.2 micromolar, more preferably 0.001-0.05 micromolar for both assays.

The term “USP25 Inhibitor” as used herein refers to a compound disclosed herein (e.g., a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of Formula (IV), a compound of Formula (V), a compound of Formula (VI), and/or a compound of Formula (VII)) having an IC₅₀ of 2 micromolar or less in the Ubiquitin-Rhodamine 110 Assay for USP25 as described in Example A-2 herein. For example, the USP25 Inhibitor can be a compound of a formula disclosed herein having an IC₅₀ value of up to 2 micromolar using the Ubiquitin-Rhodamine 110 Assay for USP25 as described in Example A-2, including IC₅₀ values ranging from 0.001-2 micromolar, preferably 0.001-0.2 micromolar, more preferably 0.001-0.05 micromolar. The USP25 Inhibitor can be a compound of a formula disclosed herein having an IC₅₀ value of up to 2 micromolar using the Ubiquitin-Rhodamine 110 Assay for USP25 as described in Example A-2, including IC₅₀ values ranging from 0.001-2 micromolar, preferably 0.001-0.2 micromolar, more preferably 0.001-0.05 micromolar. The USP25 Inhibitor can be a compound of a formula disclosed herein having an IC₅₀ values of up to 2 micromolar using both the Ubiquitin-Rhodamine 110 Assay for USP25 as described in Example A-2 and the Ubiquitin-Rhodamine 110 Assay for USP25 as described in Example A-2, including IC₅₀ values ranging from 0.001-2 micromolar, preferably 0.001-0.2 micromolar, more preferably 0.001-0.05 micromolar for both assays.

The term “USP28/25 Inhibitor” as used herein refers to a compound disclosed herein (e.g., a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of Formula (IV), a compound of Formula (V), a compound of Formula (VI), and/or a compound of Formula (VII)) that is a USP28 Inhibitor or a USP25 Inhibitor or both a USP28 Inhibitor and USP25 Inhibitor, as defined herein.

Optionally, any one or more hydrogen atoms in a compound of Formula (I), Formula (II), a compound of Formula (III), a compound of Formula (IV), a compound of Formula (V), a compound of Formula (VI), and/or a compound of Formula (VII)) can independently be replaced with deuterium or other hydrogen isotope.

In a first aspect of the disclosure, the chemical entities are chosen from compounds of Formula (I):

-   -   and pharmaceutically acceptable salts, solvates, prodrugs,         stereoisomers, and tautomers thereof, are described wherein X,         Y, R₁, R₂, R₃, R₄, and n are as described herein above.

The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated herein by reference in their entireties.

The articles “a” and “an” are used in this disclosure to refer to one or more than one (e.g., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

The term “and/or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise.

The term “optionally substituted” is understood to mean that a given chemical moiety (e.g., an alkyl group) can (but is not required to) be bonded other substituents (e.g., heteroatoms). For instance, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (e.g., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents different from hydrogen. For instance, it can, at any point along the chain be bounded to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus the term “optionally substituted” means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any further functional groups. Suitable substituents used in the optional substitution of the described groups include, without limitation, halogen, oxo, —OH, —CN, —COOH, —CH₂CN, —O—(C₁-C₆) alkyl, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, —O—(C₂-C₆) alkenyl, —O—(C₂-C₆) alkynyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, —OH, —OP(O)(OH)₂, —OC(O)(C₁-C₆) alkyl, —C(O)(C₁-C₆) alkyl, —OC(O)O(C₁-C₆) alkyl, —NH₂, —NH((C₁-C₆) alkyl), —N((C₁-C₆) alkyl)₂, —NHC(O)(C₁-C₆) alkyl, —C(O)NH(C₁-C₆) alkyl, —S(O)₂(C₁-C₆) alkyl, —S(O)NH(C₁-C₆) alkyl, and S(O)N((C₁-C₆) alkyl)₂. The substituents can themselves be optionally substituted. “Optionally substituted” as used herein also refers to substituted or unsubstituted whose meaning is described below.

As used herein, the term “substituted” means that the specified group or moiety bears one or more suitable substituents wherein the substituents may connect to the specified group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl connects to one atom of the aryl with a bond or by fusing with the aryl and sharing two or more common atoms.

As used herein, the term “unsubstituted” means that the specified group bears no substituents.

Unless otherwise specifically defined, the term “aryl” refers to cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. Exemplary substituents include, but are not limited to, —H, -halogen, —O—(C₁-C₆) alkyl, (C₁-C₆) alkyl, —O—(C₂-C₆) alkenyl, —O—(C₂-C₆) alkynyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, —OH, —OP(O)(OH)₂, —OC(O)(C₁-C₆) alkyl, —C(O)(C₁-C₆) alkyl, —OC(O)O(C₁-C₆) alkyl, —NH₂, NH((C₁-C₆) alkyl), N((C₁-C₆) alkyl)₂, —S(O)₂—(C₁-C₆) alkyl, —S(O)NH(C₁-C₆) alkyl, and —S(O)N((C₁-C₆) alkyl)₂. The substituents can themselves be optionally substituted. Furthermore when containing two fused rings the aryl groups herein defined may have an unsaturated or partially saturated ring fused with a fully saturated ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, and the like.

Unless otherwise specifically defined, “heteroaryl” means a monovalent monocyclic aromatic radical of 5 to 24 ring atoms or a polycyclic aromatic radical, containing one or more ring heteroatoms selected from N, O, and S, the remaining ring atoms being C. Heteroaryl as herein defined also means a bicyclic heteroaromatic group wherein the heteroatom is selected from N, O, and S. The aromatic radical is optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydro pyrrolo[1,2-a]pyrimidinyl, dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzooxazolyl, benzoisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, thieno[2,3-d]thiazole, 1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine, 3H-indolyl, and derivatives thereof. Furthermore the terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuran, indolinyl, indolyl, isoindolyl and dihydrobenzoxanyl.

Halogen or “halo” refers to fluorine, chlorine, bromine, or iodine.

Alkyl refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms. Examples of a (C₁-C₆) alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

“Alkoxy” refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms containing a terminal “O” in the chain, e.g., —O(alkyl). Examples of alkoxy groups include without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

The term “alkylene” or “alkylenyl” refers to a divalent alkyl radical. Any of the above mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. As herein defined, alkylene may also be a C₀-C₆ alkylene. An alkylene may further be a C₀-C₄ alkylene. Typical alkylene groups include, but are not limited to, —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂CH₂—, —CH₂CH(CH₃)—, —CH₂C(CH₃)₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and the like.

“Cycloalkyl” or “carbocyclyl” means monocyclic or polycyclic saturated carbon rings containing 3-18 carbon atoms. Examples of cycloalkyl groups include, without limitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl and derivatives thereof. A C₃-C₈ cycloalkyl is a cycloalkyl group containing between 3 and 8 carbon atoms. A cycloalkyl group can be fused (e.g., decalin) or bridged (e.g., norbornane).

“Heterocyclyl” or “heterocycloalkyl” monocyclic or polycyclic rings containing carbon and heteroatoms taken from oxygen, nitrogen, or sulfur and wherein there is not delocalized π electrons (aromaticity) shared among the entire ring carbon or heteroatoms. The heterocycloalkyl ring structure may be substituted by one or more substituents. The substituents can themselves be optionally substituted. Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetadinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, and homotropanyl. As used herein, “heterocyclyl” and “heterocycloalkyl” also includes bridged and spirocyclic ring systems where at least one atom is a heteroatom. A heterocyclic ring as a substituent may attach via a ring heteroatom (e.g. “N-linked”) or via a ring carbon (e.g. “C-linked”).

The term “hydroxyalkyl” means an alkyl group as defined above, where the alkyl group is substituted with one or more OH groups. Examples of hydroxyalkyl groups include HO—CH₂—, HO—CH₂—CH₂— and CH₃—CH(OH)—.

The term “haloalkyl” as used herein refers to an alkyl group, as defined herein, which is substituted one or more halogen. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.

The term “haloalkoxy” as used herein refers to an alkoxy group, as defined herein, which is substituted one or more halogen. Examples of haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.

The term “cyano” as used herein means a substituent having a carbon atom joined to a nitrogen atom by a triple bond, e.g., C≡N.

The term “solvate” refers to a complex of variable stoichiometry formed by a solute and solvent. Such solvents for the purpose of the disclosure may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates wherein water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water.

The term “isomer” refers to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With regard to stereoisomers, the compounds of Formula (I) may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers.

The disclosure also includes pharmaceutical compositions comprising an effective amount of a disclosed compound and a pharmaceutically acceptable carrier.

The term “treating” with regard to a subject, refers to improving at least one symptom of the subject's disorder. Treating includes curing, improving, or at least partially ameliorating the disorder.

The term “disorder” is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

The term “administer”, “administering”, or “administration” as used in this disclosure refers to either directly administering a disclosed compound or pharmaceutically acceptable salt of the disclosed compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject's body.

The term “prodrug,” as used in this disclosure, means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to a disclosed compound.

The term “cancer” includes, but is not limited to, the following cancers: bladder cancer, breast cancer (e.g., ductal carcinoma), cervical cancer (e.g.: squamous cell carcinoma), colorectal cancer (e.g., adenocarcinoma), esophageal cancer (e.g., squamous cell carcinoma), gastric cancer (e.g.: adenocarcinoma, medulloblastoma, colon cancer, choriocarcinoma, squamous cell carcinoma), head and neck cancer, hematologic cancer (e.g., acute lymphocytic anemia, acute myeloid leukemia, acute lymphoblastic B cell leukemia, anaplastic large cell lymphoma, B-cell lymphoma, Burkitt's lymphoma, chronic lymphocytic leukemia, chronic eosinophillic leukemia/hypereosinophillic syndrome, chronic myeloid leukemia, Hodgkin's lymphoma, mantle cell lymphoma, multiple myeloma, T-cell acute lymphoblastic leukemia), lung cancer (e.g., bronchioloalveolar adenocarcinoma, mesothelioma, mucoepidermoid carcinoma, small-cell lung cancer, non-small cell lung cancer, adenocarcinoma, squamous cell carcinoma), liver cancer (e.g., hepatocellular carcinoma), lymphoma, neurological cancer (e.g., glioblastoma, neuroblastoma, neuroglioma), ovarian (e.g., adenocarcinoma), pancreatic cancer (e.g., ductal carcinoma), prostate cancer (e.g., adenocarcinoma), renal cancer (e.g., renal cell carcinoma, clear cell renal carcinoma), sarcoma (e.g., chondrosarcoma, Ewings sarcoma, fibrosarcoma, multipotential sarcoma, osteosarcoma, rhabdomyosarcoma, synovial sarcoma), skin cancer (e.g., melanoma, epidermoid carcinoma, squamous cell carcinoma), thyroid cancer (e.g., medullary carcinoma), and uterine cancer.

The present disclosure relates to chemical entities chosen from compounds and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof, capable of inhibiting at least one pathway chosen from USP28 and USP25, which are useful for the treatment of diseases and disorders associated with modulation of at least one pathway chosen from USP28 and USP25. The disclosure further relates to chemical entities chosen from compounds and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof, which are useful for inhibiting at least one pathway chosen from USP28 and USP25.

In any of the embodiments as disclosed herein, the cancer can be any cancer in any organ, for example, a cancer is selected from the group consisting of glioma, thyroid carcinoma, breast carcinoma, small-cell lung carcinoma, non-small-cell carcinoma, gastric carcinoma, colon carcinoma, gastrointestinal stromal carcinoma, pancreatic carcinoma, bile duct carcinoma, CNS carcinoma, ovarian carcinoma, endometrial carcinoma, prostate carcinoma, renal carcinoma, anaplastic large-cell lymphoma, leukemia, multiple myeloma, mesothelioma, and melanoma, and combinations thereof.

The present disclosure relates to chemical entities chosen from compounds and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof, capable of inhibiting at least one pathway chosen from USP28 and USP25, which are useful for the treatment of diseases and disorders associated with modulation of at least one pathway chosen from USP28 and/or USP25 enzyme. The present disclosure further relates to chemical entities chosen from compounds and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof, which are useful for inhibiting at least one pathway chosen from USP28 and USP25.

In one embodiment, the chemical entities are chosen from compounds of Formula (II):

wherein X, Y, R₁, R₂, R₃, R₄, and n are as described herein above, and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof.

In another embodiment, the chemical entities are chosen from compounds of Formula (III):

wherein X, Y, R₁, R₂, R₃, R₄, and n are as described herein above, and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.

In another embodiment, the chemical entities are chosen from compounds of Formula (IV):

wherein X, Y, R₁, R₂, R₃, R₄, and n are as described herein above and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.

In another embodiment, the chemical entities are chosen from compounds of Formula (V):

wherein X, Y, R₁, R₂, R₃, R₄, and n are as described herein above and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.

In some embodiments, the chemical entities are chosen from compounds of Formula (VI):

-   -   or a pharmaceutically acceptable salt thereof,         wherein:     -   X is chosen from C(R)(R″) and O;     -   each of Y₁, Y₂, and Y₃ is independently chosen from C(R₃) and N;     -   R′ is chosen from H, deuterium, and CH₃;     -   each of R and R″ is independently chosen from H, halogens, —OH,         —CN, C₁-C₆ alkyl optionally substituted with one or more Ri,     -   or R and R″ together with the carbon they are attached form a         spirocyclic cyclopropyl optionally substituted with one or more         Ri, wherein any R, R″, or Ri group being or containing hydrogen         can independently have one or more hydrogen replaced with         deuterium;     -   each Ri is independently chosen from halogen, —OH, and CH₃;     -   R₁ is chosen from 6-12 membered fused and nonfused heteroaryls         optionally substituted with one or more substituent chosen from         R₅ and/or R₆, and further wherein any R₁ group containing         hydrogen can have one or more hydrogen replaced with deuterium;     -   R₂ is chosen from N-linked 4-12 membered heterocyclyls, C-linked         4-12 membered heterocyclyls, and an O linker attached to a 4-12         membered heterocyclyl, wherein the 4-12 membered heterocyclyls         are optionally substituted with one or more R₅ (which can be the         same or different from the one or more R₅ of R₁), and further         wherein any hydrogen in a R₂ group can have one or more hydrogen         replaced with deuterium;     -   each R₃ is independently chosen from H, (C₁-C₆) alkyl, (C₁-C₆)         alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH,         —CN, (C₃-C₈) cycloalkyl, heterocycloalkyl, aryl, and heteroaryl         groups, wherein each of (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)         haloalkyl, (C₁-C₆) haloalkoxy, cycloalkyl, heterocycloalkyl,         aryl, and heteroaryl groups are optionally substituted with one         or more R₇;     -   R₄ is chosen from H, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)         haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —CN, (C₃-C₈)         cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups,         wherein each of (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)         haloalkyl, (C₁-C₆) haloalkoxy, (C₃-C₈) cycloalkyl,         heterocycloalkyl, aryl, and heteroaryl are optionally         substituted with one or more R₅, and further wherein any R₄         group containing hydrogen can have one or more hydrogen replaced         with deuterium;     -   each R₅ is independently chosen from —OH, —NH₂, amido-(C₁-C₆)         alkyl, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆)         haloalkoxy, halogen, cycloalkyl, heterocycloalkyl, and         —C(O)-heterocycloalkyl groups, wherein each of —NH₂,         amido-(C₁-C₆) alkyl, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)         haloalkyl, (C₁-C₆) haloalkoxy, cycloalkyl, heterocycloalkyl, and         —C(O)— heterocycloalkyl are optionally substituted with one or         more substituent independently chosen from (C₁-C₆) alkyl,         (C₁-C₆) alkoxy, —NH₂, and —OH, and wherein any R₅ group         containing hydrogen can have one or more hydrogen replaced with         deuterium;     -   each R₆ is independently chosen from -amino alkyl-aryls, -amino         alkyl-heteroaryls, -amino alkyl-cyclyl, and -amino         alkyl-heterocyclyl groups, wherein each of the R₆ groups are         optionally substituted with one or more substituent chosen from         —OH, —NH, halogens, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, and (C₁-C₆)         haloalkyl groups, and further wherein any R₆ group containing         hydrogen can have one or more hydrogen replaced with deuterium;     -   each R₇ is independently chosen from —OH, —NH₂, (C₁-C₆) alkyl,         (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen,         cycloalkyl, —C(O)-cycloalkyl, heterocycloalkyl, and         —C(O)-heterocycloalkyl groups, wherein each of —NH₂, (C₁-C₆)         alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,         halogen, cycloalkyl, —C(O)-cycloalkyl, heterocycloalkyl, and         —C(O)-heterocycloalkyl are optionally substituted with one or         more substituent independently chosen from (C₁-C₆) alkyl,         (C₁-C₆) alkoxy, and —OH;         and

-   n is 0, 1, 2, or 3.

The compound of Formula (VI) or a pharmaceutically acceptable salt thereof, wherein:

-   -   X is chosen from C(R)(R″) and 0;     -   each of Y₁, Y₂, and Y₃ is independently chosen from C(R₃) and N;     -   R′ is chosen from H, and CH₃;     -   each of R and R″ is independently chosen from H, halogens, —OH,         —CN, C₁-C₆ alkyl optionally substituted with one or more Ri,     -   or R and R″ together with the carbon they are attached form a         spirocyclic cycloalkyl (e.g., spirocyclic cyclopropyl)         optionally substituted with one or more Ri, wherein any R, R″;     -   each Ri is independently chosen from halogen, —OH, and CH₃;     -   R₁ is chosen from a fused or nonfused heteroaryls (e.g., 6-12         membered fused or nonfused heteroaryls) optionally substituted         with one or more substituent chosen from R₅ and/or R₆ (e.g., a         6-membered nonfused heteroaryl optionally substituted with one         or more R₆);     -   R₂ is chosen from N-linked-heterocyclyls (e.g., 4-12 membered         heterocyclyls), C-linked-heterocyclyls (e.g., 4-12 membered         heterocyclyls), and O-linker-heterocyclyls (e.g., 4-12 membered         heterocyclyls such as

-   -    wherein any of the —N-linked-, —C-linked or —O-linked (e.g.,         4-12 membered) heterocyclyls is optionally substituted with one         or more R₅ (which can be the same or different from the one or         more R₅ of R₁);     -   each R₃ is independently chosen from H, (C₁-C₆) alkyl, (C₁-C₆)         alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH,         —CN, (C₃-C₈) cycloalkyl, heterocycloalkyl, aryl, and heteroaryl         groups, wherein each of (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)         haloalkyl, (C₁-C₆) haloalkoxy, cycloalkyl, heterocycloalkyl,         aryl, and heteroaryl groups are optionally substituted with one         or more R₇;     -   R₄ is chosen from H, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)         haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —CN, (C₃-C₈)         cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups,         wherein each of (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)         haloalkyl, (C₁-C₆) haloalkoxy, (C₃-C₈) cycloalkyl,         heterocycloalkyl, aryl, and heteroaryl are optionally         substituted with one or more R₅;     -   each R₅ is independently chosen from —OH, —NH₂, amido-(C₁-C₆)         alkyl, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆)         haloalkoxy, halogen, cycloalkyl, heterocycloalkyl, and         —C(O)-heterocycloalkyl groups, wherein each of —NH₂,         amido-(C₁-C₆) alkyl, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)         haloalkyl, (C₁-C₆) haloalkoxy, cycloalkyl, heterocycloalkyl, and         —C(O)— heterocycloalkyl are optionally substituted with one or         more substituent independently chosen from (C₁-C₆) alkyl,         (C₁-C₆) alkoxy, —NH₂, and —OH;     -   each R₆ is independently chosen from -amino alkyl-aryls, -amino         alkyl-heteroaryls, -amino alkyl-cyclyl, and -amino         alkyl-heterocyclyl groups, wherein each of the R₆ groups are         optionally substituted with one or more substituent chosen from         —OH, —NH, halogens, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, and (C₁-C₆)         haloalkyl groups;     -   each R₇ is independently chosen from —OH, —NH₂, (C₁-C₆) alkyl,         (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen,         cycloalkyl, —C(O)-cycloalkyl, heterocycloalkyl, and         —C(O)-heterocycloalkyl groups, wherein each of —NH₂, (C₁-C₆)         alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,         halogen, cycloalkyl, —C(O)-cycloalkyl, heterocycloalkyl, and         —C(O)-heterocycloalkyl are optionally substituted with one or         more substituent independently chosen from (C₁-C₆) alkyl,         (C₁-C₆) alkoxy, and —OH; and     -   n is 0, 1, 2, or 3.

In some embodiments, a compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V) and/or Formula (VI) above includes X (if present) as CH₂ (e.g., R and R″ are both hydrogen in Formula (VI)). In other embodiments, a compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V) and/or Formula (VI) above includes X (if present) as O.

In another embodiment, the chemical entities are chosen from compounds of Formula (VI) and pharmaceutically acceptable salts thereof, wherein:

-   -   X is chosen from C(R)(R″) and O;     -   each of Y₁, Y₂, and Y₃ is independently chosen from C(R₃) and N;     -   R′ is chosen from H and CH₃;     -   each of R and R″ is independently chosen from H, halogens, —OH,         —CN, C₁-C₆ alkyl optionally substituted with one or more Ri;

each Ri is independently chosen from halogen, —OH, and CH₃;

-   -   R₁ is chosen from 6-12 membered fused and nonfused heteroaryls         optionally substituted with one or more R₅, wherein a 6-membered         nonfused heteroaryl is substituted with one or more R₆;     -   R₂ is chosen from N-linked and C-linked 4-12 membered         heterocyclyls, wherein the 4-12 membered heterocyclyls are         optionally substituted with one or more R₅ (which can be the         same or different from the one or more R₅ of R₁);     -   each R₃ is independently chosen from H, (C₁-C₆) alkyl, (C₁-C₆)         alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, and         —CN, wherein each of (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)         haloalkyl, and (C₁-C₆) haloalkoxy groups are optionally         substituted with one or more R₇;     -   R₄ is chosen from H, (C₁-C₆) alkyl, halogen, —OH, and —CN,         wherein the (C₁-C₆) alkyls are optionally substituted with one         or more substituent independently chosen from (C₁-C₆) alkoxy and         —OH;     -   each R₅ is independently chosen from —OH, —NH₂, —NHC(O)CH₃,         (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆)         haloalkoxy, halogen, cycloalkyl, heterocycloalkyl, and —C(O)—         heterocycloalkyl groups, wherein alkyls are optionally         substituted with one or more substituent independently chosen         from (C₁-C₆) alkoxy, —NH₂, and —OH;     -   each R₆ is independently chosen from —NH(C₁-C₆)alkyl-aryls,         —NH(C₁-C₆)alkyl-heteroaryls, —NH(C₁-C₆)alkyl-cyclyl and         —NH(C₁-C₆)alkyl-heterocyclyl groups, wherein each of the R₆         groups are optionally substituted with one or more substituent         chosen from —OH, —NH, halogens, (C₁-C₆) alkyl, (C₁-C₆) alkoxy,         and (C₁-C₆) haloalkyl groups;     -   each R₇ is independently chosen from —OH, —NH₂, (C₁-C₆) alkyl,         (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen,         cycloalkyl, —C(O)-cycloalkyl, heterocycloalkyl, and         —C(O)-heterocycloalkyl groups, wherein the (C₁-C₆) alkyl,         (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen,         cycloalkyl, —C(O)-cycloalkyl, heterocycloalkyl, and —C(O)—         heterocycloalkyl groups are optionally substituted with one or         more substituent independently chosen from (C₁-C₆) alkoxy and         —OH;         and     -   n is 0, 1, 2, or 3.

In another embodiment, the chemical entities are chosen from compounds of Formula (VII):

or a pharmaceutically acceptable salt thereof, wherein

-   -   Y is chosen from C(R₃) and N;     -   R′ is chosen from H, deuterium, and CH₃;     -   R₁ is chosen from 6-11 membered heteroaryls optionally         substituted with one or more substituent chosen from R₅ and/or         R₆;     -   R₂ is chosen from N-linked 4-12 membered heterocyclyls and         C-linked 4-12 membered heterocyclyls, wherein the heterocyclyls         are optionally substituted with one or more R₅, and further         wherein any R₂ group containing hydrogen can have one or more         hydrogen replaced with deuterium;     -   each R₃ (if present) is independently chosen from H, deuterium,         (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆)         haloalkoxy, halogen, —OH, —CN, wherein each of (C₁-C₆) alkyl,         (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy,         cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are         optionally substituted with one or more R₇;     -   each R₄ is chosen from H, deuterium, (C₁-C₆) alkyl, halogen,         —OH, —CN, and further wherein any R₄ group containing hydrogen         can have one or more hydrogen replaced with deuterium;     -   each R₅ (if present) is independently chosen from —OH, —NH₂,         NHC(O)CH₃, —C(O)NHCH₃, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆)         haloalkyl, (C₁-C₆) haloalkoxy, halogen, cycloalkyl,         heterocycloalkyl, and —C(O)-heterocycloalkyl groups, wherein         each of —NH₂, —NHC(O)CH₃, —C(O)NHCH₃, (C₁-C₆) alkyl, (C₁-C₆)         alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, cycloalkyl,         heterocycloalkyl, and —C(O)-heterocycloalkyl are optionally         substituted with one or more substituent independently chosen         from (C₁-C₆) alkoxy, —NH₂, and —OH, and wherein any R₅ group         containing hydrogen can have one or more hydrogen replaced with         deuterium;     -   each R₆ (if present) is chosen from —NH(C₁-C₆)alkyl-aryls,         —NH(C₁-C₆)alkyl-heteroaryls, —NH(C₁-C₆)alkyl-heterocyclyl         groups, and —NH(C₁-C₆)alkyl-heterocyclyl groups, wherein each of         the R₆ groups are optionally substituted with one or more         substituent chosen from —OH, —NH, halogens, (C₁-C₆) alkyl,         (C₁-C₆) alkoxy, and (C₁-C₆) haloalkyl groups, and further         wherein any R₆ group containing hydrogen can have one or more         hydrogen replaced with deuterium;     -   each R₇ (if present) is independently chosen from —OH, —NH₂,         (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆)         haloalkoxy, halogen, cycloalkyl, —C(O)-cycloalkyl,         heterocycloalkyl, and —C(O)-heterocycloalkyl groups, wherein         each of —NH₂, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl,         (C₁-C₆) haloalkoxy, halogen, cycloalkyl, —C(O)— cycloalkyl,         heterocycloalkyl, and —C(O)-heterocycloalkyl are optionally         substituted with one or more substituent independently chosen         from (C₁-C₆) alkyl, (C₁-C₆) alkoxy, and —OH; and     -   n is 0, 1, 2, or 3.

In some embodiments of the Formulae above, X is CH₂. In another embodiments, X is O.

In some embodiments of the Formulae above, R₁ is chosen from 6-12 membered heteroaryls optionally substituted with one or more R₅. In some embodiments of the Formulae above, R₁ is chosen from 6 membered heteroaryls substituted with one or more R₆. In some embodiments of the Formulae above, any R₁ group or optional substituent containing hydrogen can have one or more hydrogen replaced with deuterium.

In some embodiments of the Formulae above, R₂ is chosen from N-linked 4-10 membered heterocyclyls optionally substituted with one or more R₅, and wherein a sulfur member of the heterocyclyls can be S(O) or S(O)₂. In some embodiments of the Formulae above R₂ is chosen from C-linked 4-10 membered heterocyclyls optionally substituted with one or more R₅, and wherein a sulfur member of the heterocyclyls can be S(O) or S(O)₂. In some embodiments of the Formulae above R₂ is chosen from 0 linked to a heterocyclic entity that is optionally substituted with one or more R₅, and wherein a sulfur member of the heterocyclyls can be S(O) or S(O)₂. In some embodiments of the Formulae above, any R₂ group or optional substituent containing hydrogen can have one or more hydrogen replaced with deuterium.

In some embodiments of the Formulae above, R₃ is independently chosen from H, (C₁-C₆) alkyl, (C₁-C₆) haloalkoxy, halogen, and —CN.

In some embodiments of the Formulae above, R₄ is chosen from H and (C₁-C₆) alkyls. In some embodiments of the Formulae above, one or more hydrogen of R₄ can be replaced with deuterium.

In some embodiments of the Formulae above, n is 0, 1, or 2. In another embodiment, n is 0 or 1. In yet another embodiment, n is 1, 2, or 3. In another embodiment, n is 1 or 2. In another embodiment, n is 2 or 3. In another embodiment, n is 0. In another embodiment, n is 1. In another embodiment, n is 2. In another embodiment, n is 3.

In some embodiments of the Formulae above, R₁, optionally substituted with R₅ and/or R₆, is chosen from the groups of Table A. Preferably, a compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI) and/or Formula (VII) comprises R₁ (alone or as substituted with one of more R₅ and/or R₆) that is selected from the groups in Table A below.

TABLE A

In some embodiments of the Formulae above, R₂, optionally substituted with R₅, is chosen from the groups of Table B below. Preferably, a compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI) and/or Formula (VII) can comprises R₂ (alone or as substituted with one of more R₅ and/or R₆, which can be the same or different) that is selected from the groups in Table B below.

TABLE B

Preferably, a compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI) and/or Formula (VII) can comprises both R₁ (alone or as substituted with one of more R₅ and/or R₆, which can be the same or different) that is selected from the groups in Table A above, and R₂ (alone or as substituted with one of more R₅ and/or R₆, which can be the same or different) that is selected from the groups in Table B above.

In some embodiments, the chemical entities are chosen from compounds of Formula (IIa):

or a pharmaceutically acceptable salt thereof, wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇ and n are as defined in Formula (I), and/or from compounds of Formula (IIaa):

or a pharmaceutically acceptable salt thereof, wherein R₁, R₂, R₃, R₅, R₆, R₇ and n are as defined in Formula (I). In some embodiments, the chemical entities are chosen from compounds of Formula (IIb):

-   -   or a pharmaceutically acceptable salt thereof,         wherein R′, R₁, R₂, R₃, R₄, R₅, R₆, R₇ and n are each         independently as defined Formula (VI).

In some embodiments, the chemical entities are chosen from compounds of Formula (IIaa):

-   -   or a pharmaceutically acceptable salt thereof,         wherein

-   R₁ is chosen from 8-9-membered heteroaryls substituted with one or     more substituent chosen from R₅ and R₆;

-   R₂ is chosen from N-linked 6-12 membered heterocyclyls or C-linked     6-12 membered heterocyclyls, wherein the 6-12 membered heterocyclyls     are optionally substituted with one or more R₅;

-   R₃ is independently chosen from H, (C₁-C₆) alkyl, halogen, and —CN;     and

-   wherein R₅, R₆, R₇ and n are each independently as defined in     Formula (I).

In preferred embodiments of Formula (IIaa), R₁, optionally substituted with R₅ and/or R₆, is chosen from

and

-   R₂, optionally substituted with R₅, is chosen from

In some embodiments, the chemical entities are chosen from compounds of Formula (IIb′):

-   -   or a pharmaceutically acceptable salt thereof,

-   wherein R′ is chosen from H and CH₃;

-   R₁ is chosen from 8-9 membered heteroaryls substituted with one or     more substituent chosen from R₅ and R₆;

-   R₂ is chosen from N-linked 6-12 membered heterocyclyls or C-linked     6-12 membered heterocyclyls, wherein the 6-12 membered heterocyclyls     are optionally substituted with one or more R₅;

-   R₃ is independently chosen from H and halogen; and

-   R₅, R₆, R₇ and n are each independently as defined in Formula (VI).

In preferred embodiments of Formula (IIb′), R₁, optionally substituted with R₅ and/or R₆, is chosen from

and

-   R₂, optionally substituted with R₅, is chosen from

In some embodiments, the chemical entities are chosen from compounds of Formula (IIIa):

or a pharmaceutically acceptable salt thereof,

-   wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇ and n are each independently as     defined Formula (I); and/or from compounds Formula (IIIb):

-   or a pharmaceutically acceptable salt thereof, -   wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇ and n are each independently as     defined Formula (I).

In some embodiments, the chemical entities are chosen from compounds of Formula (IIIaa):

-   or a pharmaceutically acceptable salt thereof, wherein -   R₁ is chosen from 8-11 membered heteroaryls optionally substituted     with one or more R₅; -   R₂ is chosen from N-linked 4-12 membered heterocyclyls and C-linked     4-12 membered heterocyclyls, optionally substituted with one or more     R₅; -   each R₅ (if present) is independently chosen from —OH, —NH₂,     NHC(O)CH₃, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆)     haloalkoxy, halogen, cycloalkyl, heterocycloalkyl, and     —C(O)-heterocycloalkyl groups, wherein each of —NH₂, —NHC(O)CH₃,     (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆)     haloalkoxy, cycloalkyl, heterocycloalkyl, and —C(O)—     heterocycloalkyl are optionally substituted with one or more     substituent independently chosen from (C₁-C₆) alkoxy, —NH₂, and —OH;     and -   n is 0, 1, 2, or 3.

In preferred embodiments of Formula (IIIaa), R₁ is chosen from

-   wherein B is chosen from a bond or C; -   Z is chosen from N, S, C(Rii); -   Rii is chosen from H, CH₃ and R₅; -   R₂ is chosen from N-linked 5-8 membered heterocyclyls substituted     with one to three R₅; -   each R₅ (if present) is independently chosen from —OH, —NH₂,     NHC(O)CH₃, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆)     haloalkoxy, halogen, cycloalkyl, heterocycloalkyl, and     —C(O)-heterocycloalkyl groups, wherein each of —NH₂, —NHC(O)CH₃,     (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆)     haloalkoxy, cycloalkyl, heterocycloalkyl, and —C(O)—     heterocycloalkyl are optionally substituted with one or more     substituent independently chosen from (C₁-C₆) alkoxy, —NH₂, and —OH;     and -   n is 0, 1, 2, or 3.

In further preferred embodiments of Formula (IIIaa), R₁, optionally substituted with R₅, is chosen from

and

-   R₂, optionally substituted with R₅, is chosen from

In some embodiments, the chemical entities are chosen from compounds of Formula (IVa):

-   or a pharmaceutically acceptable salt thereof, -   wherein R₁, R₂, R₄, R₅, R₆, R₇ and n are each independently as     defined Formula (I).

In some embodiments, the chemical entities are chosen from compounds of Formula (Va):

-   or a pharmaceutically acceptable salt thereof, -   wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇ and n are each independently as     defined Formula (I).

In some embodiments, the chemical entity is chosen from compounds of Formula (Vaa):

-   or a pharmaceutically acceptable salt thereof, -   wherein R₁ is chosen from 8-membered heteroaryls substituted with     one or more substituent chosen from R₅ and R₆; R₂ is chosen from     N-linked 5-membered heterocyclyls; and R₅, R₆, R₇ and n are each     independently as defined Formula (I).

In further preferred embodiments of Formula (Vaa), R₁ substituted with R₅ is chosen from

and R₂ is chosen from

In some embodiments, the chemical entities are chosen from compounds of Formula (VIIa′):

-   or a pharmaceutically acceptable salt thereof, -   wherein R′, R₁, R₂, R₃, R₄, R₅, R₆, R₇ and n are each independently     as defined Formula (VI).

In at least one embodiment, the chemical entities are chosen from compounds of Formula (VIIaa):

-   or a pharmaceutically acceptable salt thereof, wherein -   R₁ is chosen from 8-9 membered heteroaryls optionally substituted     with one or more R₅; -   R₂ is chosen from N-linked 4-12 membered heterocyclyls optionally     substituted with one or more R₅; -   each R₅ (if present) is independently chosen from —OH, —NH₂,     NHC(O)CH₃, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆)     haloalkoxy, halogen, cycloalkyl, heterocycloalkyl, and     —C(O)-heterocycloalkyl groups, wherein each of —NH₂, —NHC(O)CH₃,     (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆)     haloalkoxy, cycloalkyl, heterocycloalkyl, and —C(O)—     heterocycloalkyl are optionally substituted with one or more     substituent independently chosen from (C₁-C₆) alkoxy, —NH₂, and —OH;     and -   n is 0, 1, 2, or 3.

In preferred embodiments of Formula (VIIaa), R₁ is chosen from

-   wherein B is chosen from a bond or C; -   Z is chosen from N, S, C(Rii); -   Rii is chosen from H, CH₃ and R₅; -   R₂ is chosen from N-linked 5-8 membered heterocyclyls substituted     with one to three R₅; -   each R₅ (if present) is independently chosen from —OH, —NH₂,     NHC(O)CH₃, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆)     haloalkoxy, halogen, cycloalkyl, heterocycloalkyl, and     —C(O)-heterocycloalkyl groups, wherein each of —NH₂, —NHC(O)CH₃,     (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆)     haloalkoxy, cycloalkyl, heterocycloalkyl, and —C(O)—     heterocycloalkyl are optionally substituted with one or more     substituent independently chosen from (C₁-C₆) alkoxy, —NH₂, and —OH;     and -   n is 0, 1, 2, or 3.

In further preferred embodiments of Formula (VIIaa), R₁, optionally substituted with R₅, is chosen from

and

-   R₂, optionally substituted with R₅, is chosen from

Preferably, the compound is a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (IIa), (IIaa), (IIb′), (IIIa), (IIIb), (IIIaa), (IVa), (Va), (Vaa), (VIIa′) or Formula (VIIaa) that is USP28 Inhibitor, a USP25 Inhibitor and/or a USP 28/25 Inhibitor as defined herein.

In another embodiment of the disclosure, the compounds of Formula (I) are enantiomers. In some embodiments the compounds are the (S)-enantiomer. In other embodiments the compounds are the (R)-enantiomer. In yet other embodiments, the compounds of Formula (I) may be (+) or (−) enantiomers.

It should be understood that all isomeric forms are included within the present disclosure, including mixtures thereof. If the compound contains a double bond, the substituent may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans configuration. All tautomeric forms are also intended to be included.

Compounds of the disclosure, and pharmaceutically acceptable salts, hydrates, solvates, stereoisomers and prodrugs thereof may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present disclosure.

The compounds of the disclosure may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the disclosure as well as mixtures thereof, including racemic mixtures, form part of the present disclosure. In addition, the present disclosure embraces all geometric and positional isomers. For example, if a compound of the disclosure incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the disclosure. Each compound herein disclosed includes all the enantiomers that conform to the general structure of the compound. The compounds may be in a racemic or enantiomerically pure form, or any other form in terms of stereochemistry. The assay results may reflect the data collected for the racemic form, the enantiomerically pure form, or any other form in terms of stereochemistry.

Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of the disclosure may be atropisomers (e.g., substituted biaryls) and are considered as part of this disclosure. Enantiomers can also be separated by use of a chiral HPLC column.

It is also possible that the compounds of the disclosure may exist in different tautomeric forms, and all such forms are embraced within the scope of the disclosure. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the disclosure.

All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this disclosure, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the disclosure. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the disclosure.) Individual stereoisomers of the compounds of the disclosure may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present disclosure can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms “salt”, “solvate”, “ester,” “prodrug” and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the compounds disclosed herein.

The compounds disclosed herein may form salts which are also within the scope of this disclosure.

The present disclosure relates to compounds which are modulators of at least one pathway chosen from USP28 and USP25. In one embodiment, the compounds of the present disclosure are inhibitors of at least one pathway chosen from USP28 and USP25.

The present disclosure is directed to chemical entities chosen from compounds as described herein and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof, and pharmaceutical compositions comprising at least one chemical entity chosen from compounds as described herein, and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.

Another aspect of the disclosure relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder associated with modulation of USP28. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of USP28 an effective amount the compositions and chemical entities of Formula (I). In one embodiment, the disease or disorder is cancer.

In another aspect, the present disclosure is directed to a method of treating, preventing, inhibiting, or eliminating a disease or disorder associated with inhibition of USP28. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of USP28 an effective amount the compositions and chemical entities of Formula (I). In one embodiment, the disease or disorder is cancer.

In another aspect, the present disclosure is directed to a method of inhibiting USP28. The method involves administering to a patient in need thereof an effective amount of a chemical entity of Formula (I).

Another aspect of the disclosure relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder associated with modulation of USP25. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of USP25 an effective amount the compositions and chemical entities of Formula (I). In one embodiment, the disease or disorder is cancer.

In another aspect, the present disclosure is directed to a method of treating, preventing, inhibiting, or eliminating a disease or disorder associated with inhibition of USP25. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of USP25 an effective amount the compositions and chemical entities of Formula (I). In one embodiment, the disease or disorder is cancer.

In another aspect, the present disclosure is directed to a method of inhibiting USP25. The method involves administering to a patient in need thereof an effective amount of a chemical entity of Formula (I).

Another aspect of the disclosure relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder associated with modulation of USP28. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of USP28 an effective amount the compositions and chemical entities of Formula (I). In one embodiment, the disease or disorder is cancer. In another aspect, the present disclosure is directed to a method of treating, preventing, inhibiting, or eliminating a disease or disorder associated with inhibition of USP28. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of USP28 an effective amount the compositions and chemical entities of Formula (I). In one embodiment, the disease or disorder is cancer. The method can comprise administering to a patient in need of a treatment for diseases or disorders associated with modulation of USP28 and/or USP25 an effective amount of a pharmaceutical composition comprising a USP28 Inhibitor, USP25 Inhibitor, and/or USP28/25 Inhibitor as disclosed herein. In another aspect, the present disclosure is directed to a method of inhibiting at least one pathway chosen from USP28 and USP25. The method involves administering to a patient in need thereof an effective amount of a chemical entity of Formula (I). The method can comprise administering to a patient in need of a treatment for diseases or disorders associated with modulation of USP28 and/or USP25 an effective amount of a pharmaceutical composition comprising a USP28 Inhibitor, USP25 Inhibitor, and/or USP28/25 Inhibitor as disclosed herein.

Another aspect of the present disclosure relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder in a patient associated with the inhibition of USP28, the method comprising administering to a patient in need thereof an effective amount of a chemical entity of Formula (I). In one embodiment, the disease or disorder is cancer. The method can comprise administering to a patient in need of a treatment for diseases or disorders associated with modulation of USP28 and/or USP25 an effective amount of a pharmaceutical composition comprising a USP28 Inhibitor, USP25 Inhibitor, and/or USP28/25 Inhibitor as disclosed herein.

Another aspect of the present disclosure relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder in a patient associated with the inhibition of USP25, the method comprising administering to a patient in need thereof an effective amount of a chemical entity of Formula (I). In one embodiment, the disease or disorder is cancer. The method can comprise administering to a patient in need of a treatment for diseases or disorders associated with modulation of USP28 and/or USP25 an effective amount of a pharmaceutical composition comprising a USP28 Inhibitor, USP25 Inhibitor, and/or USP28/25 Inhibitor as disclosed herein.

Another aspect of the present disclosure relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder in a patient associated with the inhibition of at least one pathway chosen from USP28 and USP25, the method comprising administering to a patient in need thereof an effective amount of a chemical entity of Formula (I). In one embodiment, the disease or disorder is cancer. The method can comprise administering to a patient in need of a treatment for diseases or disorders associated with modulation of USP28 and/or USP25 an effective amount of a pharmaceutical composition comprising a USP28 Inhibitor, USP25 Inhibitor, and/or USP28/25 Inhibitor as disclosed herein.

In another aspect, the present disclosure relates to a method of treating, preventing, inhibiting, or eliminating cancer. The method comprises administering to a patient in need of a treatment for cancer an effective amount of a chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof. The method can comprise administering to a patient in need of a treatment for diseases or disorders associated with modulation of USP28 and/or USP25 an effective amount of a pharmaceutical composition comprising a USP28 Inhibitor, USP25 Inhibitor, and/or USP28/25 Inhibitor as disclosed herein.

Another aspect of the present disclosure relates to a chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof, for use in a method of treating, preventing, inhibiting, or eliminating a disease or disorder associated with inhibiting USP28. In one embodiment, the disease or disorder is cancer. The method can comprise administering to a patient in need of a treatment for diseases or disorders associated with modulation of USP28 and/or USP25 an effective amount of a pharmaceutical composition comprising a USP28 Inhibitor, USP25 Inhibitor, and/or USP28/25 Inhibitor as disclosed herein.

In another aspect, the present disclosure relates to a chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof, for use in a method of treating, preventing, inhibiting, or eliminating a disease or disorder associated with inhibiting USP25. In one embodiment, the disease or disorder is cancer.

Another aspect of the present disclosure relates to a chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof, for use in a method of treating, preventing, inhibiting, or eliminating a disease or disorder associated with inhibiting at least one pathway chosen from USP28 and USP25. In one embodiment, the disease or disorder is cancer.

In another aspect, the present disclosure relates to a chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof, for use in a method for treating, preventing, inhibiting, or eliminating cancer.

Another aspect of the present disclosure relates to the use of a chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof, in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a disease or disorder associated with inhibiting USP28. In one embodiment, the disease or disorder is cancer.

Another aspect of the present disclosure relates to the use of a chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof, in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a disease or disorder associated with inhibiting at least one pathway chosen from USP28 and USP25. In one embodiment, the disease or disorder is cancer.

In another aspect, the present disclosure relates to the use of a chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof, in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating cancer.

In other embodiments, the present disclosure relates to the use of an inhibitor of USP28 for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of a disease or disorder associated with cancer.

The present disclosure also relates to the use of an inhibitor of USP28 for the preparation of a medicament used in the treatment, prevention, inhibition, or elimination of a disease or condition mediated by USP28, wherein the medicament comprises a chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof. The present disclosure also relates to the use of an inhibitor of USP28 for the preparation of a medicament used in the treatment, prevention, inhibition, or elimination of a disease or condition mediated by USP28, wherein the medicament comprises a chemical entity chosen from compounds of Formulae (II), (III), (IV), (V), (VI), (VII), (IIa), (IIaa), (IIb′), (IIIa), (IIIb), (IIIaa), (IVa), (Va), (Vaa), (VIIa′) or Formula (VIIaa) that is USP28 Inhibitor, a USP25 Inhibitor and/or a USP 28/25 Inhibitor as defined herein.

The present disclosure also relates to the use of an inhibitor of USP25 for the preparation of a medicament used in the treatment, prevention, inhibition, or elimination of a disease or condition mediated by USP25, wherein the medicament comprises a chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof. The present disclosure also relates to the use of an inhibitor of USP25 for the preparation of a medicament used in the treatment, prevention, inhibition, or elimination of a disease or condition mediated by USP25, wherein the medicament comprises a chemical entity chosen from compounds of Formulae (II), (III), (IV), (V), (VI), (VII), (IIa), (IIaa), (IIb′), (IIIa), (IIIb), (IIIaa), (IVa), (Va), (Vaa), (VIIa′) or Formula (VIIaa) that is USP28 Inhibitor, a USP25 Inhibitor and/or a USP 28/25 Inhibitor as defined herein.

In another aspect, the present disclosure relates to a method for the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a disease or condition mediated by at least one pathway chosen from USP28 and USP25, wherein the medicament comprises a chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof. These mechanisims have been shown to be useful in treating cancer such as lung cancer and brain cancer.

In some embodiments, the patient is selected for treatment based on gene amplification and/or elevated tumor expression of USP28, MYC, LSD1, NICD1, and/or reduced expression of FBXW7 relative to tissue-matched expression.

In some embodiments, the patient is selected for treatment based on gene amplification and/or elevated tumor expression of USP28, USP25, MYC, LSD1, NICD1, and/or reduced expression of FBXW7 relative to tissue-matched expression.

In some embodiments, administration of a compound of Formula (I) or a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable carrier induces a change in the cell cycle, cell viability, cell apoptosis, or differentiation.

For example, the change in the cell cycle or cell viability or differentiation may be indicated by decreased tumor levels of MYC, LSD1, NICD1, PIM1, CDK1, POLA2, HEY1, and/or CCND1, and/or increased levels of CD86, p21, LGALS4, and/or DLL1.

Another aspect of the disclosure is directed to pharmaceutical compositions comprising a chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant. Another aspect of the disclosure is directed to pharmaceutical compositions comprising a chemical entity chosen from compounds of Formulae (II), (III), (IV), (V), (VI), (VII), (IIa), (IIaa), (IIb′), (IIIa), (IIIb), (IIIaa), (IVa), (Va), (Vaa), (VIIa′) or Formula (VIIaa) that is USP28 Inhibitor, a USP25 Inhibitor and/or a USP 28/25 Inhibitor as defined herein.

In one embodiment, are provided methods of treating a disease or disorder associated with modulation of USP28 including cancer comprising administering to a patient suffering from at least one of said diseases or disorder a chemical entity of Formula (I). The methods of treating a disease or disorder associated with modulation of USP28 including cancer can comprise administering to a patient suffering from at least one of said diseases or disorder a chemical entity of Formulae (II), (III), (IV), (V), (VI), (VII), (IIa), (IIaa), (IIb′), (IIIa), (IIIb), (IIIaa), (IVa), (Va), (Vaa), (VIIa′) or Formula (VIIaa) that is USP28 Inhibitor, a USP25 Inhibitor and/or a USP 28/25 Inhibitor as defined herein.

In another embodiment, are provided methods of treating a disease or disorder associated with modulation of USP25 including cancer, comprising administering to a patient suffering from at least one of said diseases or disorder a chemical entity of Formula (I). The methods of treating a disease or disorder associated with modulation of USP25 including cancer, can comprise administering to a patient suffering from at least one of said diseases or disorder a chemical entity of Formulae (II), (III), (IV), (V), (VI), (VII), (IIa), (IIaa), (IIb′), (IIIa), (IIIb), (IIIaa), (IVa), (Va), (Vaa), (VIIa′) or Formula (VIIaa) that is USP28 Inhibitor, a USP25 Inhibitor and/or a USP 28/25 Inhibitor as defined herein.

In another embodiment, are provided methods of treating a disease or disorder associated with modulation of at least one pathway chosen from USP28 and USP25 including cancer, comprising administering to a patient suffering from at least one of said diseases or disorder a chemical entity of Formula (I). The methods of treating a disease or disorder associated with modulation of at least one pathway chosen from USP28 and USP25 including cancer, can also comprise administering to a patient suffering from at least one of said diseases or disorder a chemical entity of Formulae (II), (III), (IV), (V), (VI), (VII), (IIa), (IIaa), (IIb′), (IIIa), (IIIb), (IIIaa), (IVa), (Va), (Vaa), (VIIa′) or Formula (VIIaa) that is USP28 Inhibitor, a USP25 Inhibitor and/or a USP 28/25 Inhibitor as defined herein.

One therapeutic use of the compounds or compositions of the present disclosure which inhibit USP28 is to provide treatment to patients or subjects suffering from cancer.

Another therapeutic use of the compounds or compositions of the present disclosure which inhibit USP25 is to provide treatment to patients or subjects suffering from cancer.

Another therapeutic use of the compounds or compositions of the present disclosure which inhibit at least one pathway chosen from USP28 and USP25 is to provide treatment to patients or subjects suffering from cancer.

The compounds of the disclosure can be administered in effective amounts to treat or prevent a disorder and/or prevent the development thereof in subjects.

Administration of the disclosed compounds can be accomplished via any mode of administration for therapeutic agents.

Another aspect of the disclosure is directed to pharmaceutical compositions comprising a chemical entity chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, and tautomers thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

The dosage regimen utilizing the disclosed compound is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the patient; and the particular disclosed compound employed. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.

Non-limiting examples of compounds according to Formulae (I)-(VII) of the disclosure include those of Tables 9-25 below.

Method of Synthesizing the Compounds

The compounds of the present disclosure can be prepared in a number of ways known to those skilled in the art of organic synthesis. The compounds of the present disclosure may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the Schemes provided herein. The compounds disclosed herein may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes. In the schemes described herein, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and order of their execution, shall be consistent with the preparation of compounds disclosed herein (including, e.g., compounds of Formula (I)).

The compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and/or enzymatic processes. Those skilled in the art will recognize if a stereocenter exists in the compounds disclosed herein. Accordingly, the present disclosure includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but the individual enantiomers and/or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, “Stereochemistry of Organic Compounds” by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).

By way of example, compounds of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereof as appreciated by those skilled in the art. Preferred methods include but are not limited to those methods described below. General procedures to prepare compounds of the instant invention are described in General Scheme 1. An appropriately substituted and protected bicyclic intermediate 1 can be reacted with an appropriately substituted protected amine intermediate 2 under palladium-catalyzed carbon-nitrogen coupling protocols using an appropriate palladium complex, ligand, and base (such as but not limited to: RuPhos 3^(rd) generation palladium precatalyst and cesium carbonate) in a suitable solvent such as toluene at an appropriate temperature (such as 100° C.) to afford intermediate 3. The protecting group 1 (PG₁; typically a Cbz group) can be removed under suitable deprotection conditions (such as but not limited to: hydrogen (gas), with palladium on carbon in an appropriate solvent such as methanol, ethanol, or ethyl acetate) to afford amine intermediate 4. The suitably substituted amine intermediate 4 can be reacted with a suitably substituted carboxylic acid under amide coupling conditions (such as but not limited to: the coupling reagents EDC and HOBt with an appropriate base such as Et3N or DIEA in a solvent such as DMF or DMA) to afford the penultimate amide intermediate 5. The protecting group 2 (PG₂; typically a boc group) can be removed under appropriate conditions such as TFA in a solvent such as DCM or HCl in a solvent such as MeOH or dioxane to afford the final compounds 6. The final compounds can be typically purified by preparative HPLC and isolated as the free base. In the case where mixtures of enantiomers and/or diastereomers are formed, the individual stereoisomers can be purified at an appropriate stage, in many cases by chiral HPLC.

General Methods for the Preparation of Selected Intermediates

General procedures to prepare intermediates of the instant invention are described in Intermediate General Scheme 1. An appropriately substituted leaving group containing starting material 1 (LGi; typically a bromide) can be reacted with the lithiated chiral auxiliary 2 (formed by reacting 2 with a strong base such as nBuLi) in an appropriate solvent such as THF at low temperature (typically −78° C.) to afford intermediate 3. Hydrolysis to remove the auxiliary under conditions such as aqueous HCl in a solvent such as acetonitrile, followed by reduction (typically using NaBH₄ in a solvent such as MeOH) can afford amino alcohol 4. Amino alcohol 4 can be cyclized using a strong base such as NaH in a solvent such as DMSO at low temperature (typically −70° C.) to afford Intermediate 4. Addition of an appropriate protecting group (PG₁; typically a CBz group) to the corresponding intermediate can result in an appropriately substituted bicyclic intermediate 5.

General procedures to prepare intermediates of the instant invention are described in Intermediate General Scheme 2. An appropriately substituted ketone 1 can be reacted under reductive amination conditions (typically with ammonium acetate as the amine source, NaBH₃CN as the reductant, and a solvent such as MeOH) to afford the amine intermediate 2. Amine 2 is then protected (PG₁; typically a CBz group) to afford the appropriately substituted intermediate 3.

General procedures to prepare intermediates of the instant invention are described in Intermediate General Scheme 3. Acid chloride 1 can be reacted under a lewis acid promoted ethylene addition (typically using AlCl₃ and ethylene gas in a solvent such as DCM) to afford ketone 2. Ketone 2 can then either be converted to an oxime then reduced (using 0-Methylhydroxylamine hydrochloride, pyridine and EtOH to form the oxime; reduction using hydrogen gas, Raney Ni in EtOH solvent) or reacted under reductive amination conditions (typically with ammonium acetate as the amine source, NaBH₃CN as the reductant, and a solvent such as MeOH) to afford amine 3. Amine 3 can be then protected (PG₁; typically a CBz group) to afford the appropriately substituted intermediate 4.

General procedures to prepare intermediates of the instant invention are described in Intermediate General Scheme 4. 2-Pyridone 2 can be obtained by the Michael addition of enamino ketone (typically generated in situ by treatment of a mono-protected cyclohexane-1,4-dione such as 1 with ammonia in methanol) with propynoic ester. Pyridone 2 can be converted to incorporate a leaving group (LG; typically a triflate group which can be obtained by treatment with triflic anhydride in the presence of a base, such as triethylamine). Following removal of the ketone protecting group, ketone 4 can then be reacted under reductive amination conditions (typically with ammonium acetate as the amine source, NaBH₃CN as the reductant, and a solvent such as MeOH) to afford amine 5. Amine 5 can be then protected (PG₁; typically a Cbz group) to afford the appropriately substituted intermediate 6.

General procedures to prepare intermediates of the instant invention are described in Intermediate General Scheme 5. Ketone 1 can be condensed with dimethyl-formamide dimethyl acetal in a solvent (such as toluene) to provide enamino ketone 2. Ketone 2 can be treated with quinidine and a base (such as sodiumethoxide) to provide pyrimidin-2-amine 3. Pyrimidin-2-amine 3 can be converted to incorporate a leaving group (LG; typically a chloride group which can be obtained by treatment with CuCl₂ and tert-butyl nitrite) to afford the appropriately substituted intermediate 4.

General procedures to prepare intermediates of the instant invention are described in Intermediate General Scheme 6. An appropriately substituted intermediate 1 can be reacted with an appropriately substituted boronic ester 2 (or boronic acid) under palladium catalyzed carbon-carbon bond forming conditions (using an appropriate palladium catalyst such as Pd(dppf)Cl₂ dichloromethane complex) in a solvent such as 1,4-dioxane/water mixture, and a base such as potassium carbonate at a temperature such as 100° C.) to afford the coupled intermediate 3. The olefin double bond present in intermediate 3 can then be functionalized using standard methods such as but not limited to: olefin reduction and epoxidation followed by reduction of the resultant epoxide to afford an appropriately substituted intermediate 4.

General procedures to prepare intermediates of the instant invention are described in Intermediate General Scheme 7. An appropriately substituted intermediate 1 can be reacted under palladium-catalyzed boronic ester forming conditions (using a palladium catalyst such as Pd(dppf)Cl₂—CH₂Cl₂ complex and a boronic ester source such as Bis(pinacolato)diboron in a solvent such as dioxane at a temperature such as 80° C.) to afford the boronic ester 2. Boronic ester 2 can be reacted in the presence of a suitable oxidant (such as urea-hydrogen peroxide complex in a solvent such as MeOH) to afford the phenol intermediate 3. The phenol intermediate can then be alkylated with a suitable electrophile (for example by using Mitsonobu-type conditions: such as DIAD with PPh₃) to afford the appropriately substituted intermediate 4.

EXAMPLES

The disclosure is further illustrated by the following examples and synthesis schemes, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and/or scope of the appended claims.

Analytical Methods, Materials, and Instrumentation

Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Unless otherwise noted, reactions were conducted under an inert atmosphere of nitrogen. Proton nuclear magnetic resonance (NMR) spectra were obtained on either Bruker or Varian spectrometers at 300 or 400 MHz. Spectra are given in ppm (δ) and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard. Purity and mass spectral data were measured using one of the two following methods. Method 1: Waters Acquity i-class ultra-performance liquid chromatography (UPLC) system with Acquity Photo Diode Array Detector, Acquity Evaporative Light Scattering Detector (ELSD) and Waters ZQ Mass Spectrometer. Data was acquired using Waters MassLynx 4.1 software and purity characterized by UV wavelength 220 nm, evaporative light scattering detection (ELSD) and electrospray positive ion (ESI). (Column: Acquity UPLC BEH C18 1.7 μm 2.1×50 mm; Flow Rate 0.6 mL/min; Solvent A (95/5/0.1%: 10 mM Ammonium Formate/Acetonitrile/Formic Acid), Solvent B (95/5/0.09%: Acetonitrile/Water/Formic Acid); gradient: 5-100% B from 0 to 2 mins, hold 100% B to 2.2 min and 5% B at 2.21 min). Method 2: SHIMADZU LCMS consisting of an UFLC 20-AD and LCMS 2020 MS detector. (Column: Shim-pack XR-ODS, 2.2 μm, 3.0×50 mm; Solvent: (acetonitrile/water, containing 0.05% NH₄HCO₃)). Preparatory HPLC purifications were conducted as designated below with a Flow Rate of 20 mL/min and detection by UV wavelength 220 nm and 254 nm, unless otherwise noted. The absolute configuration of the separated enantiomers of the compounds in the examples described herein was occasionally determined. In all other cases the absolute configuration of the separated enantiomers was not determined and in those instances the configuration of the resolved materials were arbitrarily assigned as R or S in each case.

Abbreviations used in the following examples and elsewhere herein are: Abbr Name ACN acetonitrile atm atmospheres Boc t-butoxycarbonyl BOP (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate CbzCl benzyl chloroformate CDCl₃ deuterated chloroform CH₂Cl₂ methylene chloride, dichloromethane CO (g) carbon monoxide gas Cs₂CO₃ cesium carbonate DAST diethylaminosulfur trifluoride DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCM methylene chloride, dichloromethane DIEA diisopropylethylamine DMA N,N-dimethylacetamide DMF N,N-dimethylformamide DMSO dimethylsulfoxide DPPA diphenylphosphoryl azide EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide ESI electrospray ionization Et₂O diethyl ether Et₃N triethylamine EtOAc ethyl acetate EtOH ethanol h hours H₂O water HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate HBTU N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate HCl hydrochloric acid HMTA hexamethylenetetramine HOBt hydroxybenzotriazole IPA isopropanol K₂CO₃ potassium carbonate LDA lithium diisopropylamide m-CPBA 3-chloroperbenzoic acid MeOH methanol MgSO₄ magnesium sulfate min minutes MS mass spectrometry MsCl methanesulfonyl chloride MTBE methyl tert-butyl ether Na₂CO₃ sodium carbonate Na₂SO₄ sodium sulfate NaH sodium hydride NaHCO₃ sodium bicarbonate NaOH sodium hydroxide NBS N-bromosuccinimide NH₂OH—HCl hydroxylamine hydrochloride NH₄Cl ammonium chloride NH₄HCO₃ ammonium bicarbonate NH₄OH ammonium hydroxide NMP N-methyl-2-pyrrolidone NMR nuclear magnetic resonance Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl₂ [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(dppf)Cl₂—CH₂Cl₂  [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-DCM adduct Pd/C palladium on carbon Pd(OAc)₂ palladium(II) acetate pet. ether petroleum ether prep-HPLC preparatory high pressure liquid chromatography prep-TLC preparatory thin layer chromatography PTSA p-Toluenesulfonic acid RT retention time RuPhos 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl RuPhos Pd G3 (2-Dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′- amino-1,1′-biphenyl)]palladium(II) methanesulfonate SFC supercritical fluid chromatography TBS tert-butyl(dimethyl)silyl t-BuOH tert-butanol t-BuOK potassium tert-butoxide t-BuXPhos Pd G4 methanesulfonato(2-di-t-butylphosphino-2′,4′,6′-tri-i-propyl-1,1′- biphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II) DCM adduct TEDA triethylenediamine TFA trifluoroacetic acid TFAA trifluoroacetic anhydride THF THF XPhos Pd G3 (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′- amino-1,1′-biphenyl)]palladium(II) methanesulfonate Preparation of Intermediates

Step 1. 7-Bromo-3-nitro-2H-chromene

A mixture of 4-bromo-2-hydroxybenzaldehyde (21.6 g, 108 mmol), 1,3-dihydro-2-benzofuran-1,3-dione (32 g, 216 mmol) and dibutylamine (7.0 g, 54 mmol) in toluene (800 mL) was heated to reflux under an atmosphere of N₂. 2-Nitroethan-1-amine (50 g, 550 mmol) was added in portions over 2 h. The mixture was stirred at reflux overnight using a Dean-Stark apparatus. After cooling to room temperature, the solids were filtered out. Eight batches were thus run in parallel and the filtrate from the eight batches were combined and concentrated under vacuum. The residue was diluted with EtOAc (2 L) and washed with 1N NaOH (2 L). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:6 EtOAc/pet. ether) afforded 7-bromo-3-nitro-2H-chromene as a yellow solid. MS: (ESI, m/z): 256, 258 [M+H]⁺.

Step 2. 7-Bromochroman-3-amine

To a solution of 7-bromo-3-nitro-2H-chromene (27 g, 106 mmol) in THF (300 mL) were added BH3 (1M in THF, 600 mL, 600 mmol) and NaBH₄ (201 mg, 5.3 mmol). The mixture was stirred overnight at 65° C. After cooling to room temperature, the reaction was then quenched by the addition of 600 mL of MeOH and stirred for 8 h at 80° C. After cooling to room temperature, the mixture was concentrated under vacuum. The residue was purified by reverse phase chromatography (Column: C₁₈ silica gel; Mobile phase A: water (10 mM NH₄HCO₃), B: ACN; Gradient: 0% to 50% B over 40 min) to afford 7-bromochroman-3-amine as a white solid. MS: (ESI, m/z): 228, 230 [M+H]⁺.

Step 3. Benzyl (7-bromochroman-3-yl)carbamate (Intermediate 1)

A solution of K₂CO₃ (19.3 g, 140 mmol) in water (150 mL) was added to a solution of 7-bromochroman-3-amine (16.0 g, 70.1 mmol) in EtOAc (300 mL). Benzyl chloroformate (17.8 g, 104 mmol) was added at −10° C. and the reaction mixture was stirred for 30 min at room temperature. The mixture was diluted with EtOAc (200 mL). The organic layer was collected, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was washed with 1:1 EtOAc/pet. ether (200 mL) to give benzyl-(7-bromochroman-3-yl)carbamate as a white solid. MS: (ESI, m/z): 362, 364 [M+H]⁺.

Step 4. Benzyl (R)-(7-bromochroman-3-yl)carbamate (Intermediate 2) and Benzyl (S)-(7-bromochroman-3-yl)carbamate (Intermediate 3)

The racemate benzyl (7-bromochroman-3-yl)carbamate (12.5 g, 34.6 mmol) was separated by SFC (Column: ChiralArt Amylose-SA, 2×25 cm, 5 μm; Mobile phase A: CO₂, 80%, B: EtOH, 20%; Flow rate: 40 mL/min) to afford the title compounds as follows: benzyl (R)-(7-bromochroman-3-yl)carbamate (first eluting isomer, RT=7.98 min) as a white solid and benzyl (S)-(7-bromochroman-3-yl)carbamate (second eluting isomer, RT=9.21 min) as a white solid.

-   First eluting isomer: ¹H NMR (CDCl₃, 400 MHz) δ(ppm): 7.35-7.32 (m,     5H), 7.03-7.01 (m, 2H), 6.90 (d, J=8.8 Hz, 1H), 5.22-5.10 (m, 3H),     4.25 (s, 1H), 4.17-4.09 (m, 2H), 3.04 (dd, J=16.8 Hz, 4.8 Hz, 1H),     2.73 (d, J=16.8 Hz, 1H). MS: (ESI, m/z): 362, 364 [M+H]⁺. -   Second eluting isomer: ¹H NMR (CDCl₃, 400 MHz) δ (ppm): 7.35-7.32     (m, 5H), 7.03-7.01 (m, 2H), 6.90 (d, J=8.8 Hz, 1H), 5.22-5.07 (m,     3H), 4.25 (s, 1H), 4.18-4.09 (m, 2H), 3.04 (dd, J=16.8 Hz, 4.8 Hz,     1H), 2.73 (d, J=16.80 Hz, 1H). MS: (ESI, m/z): 362, 364 [M+H]⁺.

Step 1. 3,4-Difluoro-2-hydroxybenzaldehyde

Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was added a 2,3-difluorophenol (10.0 g, 75.33 mmol), ACN (200 mL), HCHO (23.06 g, 738 mmol), Et₃N (21.0 mL, 146 mmol), and MgCl₂ (14.6 g, 150.28 mmol). The resulting solution was stirred for 16 h at 60° C. The reaction mixture was cooled to 26° C., then was diluted with 200 mL of water. The resulting solution was extracted with ethyl acetate (3×100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford a residue that was purified by silica gel chromatography with ethyl acetate/pet. ether (1:4) to afford 3,4-difluoro-2-hydroxybenzaldehyde as light yellow oil.

Step 2. Tert-Butyl 4-(2-fluoro-4-formyl-3-hydroxyphenyl)piperazine-1-carboxylate

Into a 250-mL round-bottom flask was added 3,4-difluoro-2-hydroxybenzaldehyde (5 g, 31.63 mmol), tert-butyl piperazine-1-carboxylate (5.9 g, 31.68 mmol), DMSO (100 mL), and DIEA (6.1 g, 47.20 mmol). The resulting solution was stirred for 6 h at 120° C. After cooling to room temperature, the reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with ethyl acetate (3×100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford a residue that was purified by silica gel chromatography with ethyl acetate/pet. ether (0-30%) to afford tert-butyl 4-(2-fluoro-4-formyl-3-hydroxyphenyl)piperazine-1-carboxylate as yellow oil.

Step 3. Tert-Butyl 4-(8-fluoro-3-nitro-2H-chromen-7-yl)piperazine-1-carboxylate

Into a 100-mL round-bottom flask was added tert-butyl 4-(2-fluoro-4-formyl-3-hydroxyphenyl)piperazine-1-carboxylate (185 mg, 0.48 mmol), 1,3-dihydro-2-benzofuran-1,3-dione (166 mg, 1.06 mmol, 95%), 2-nitroethan-1-ol (104 mg, 1.08 mmol), dibutylamine (37 mg, 0.27 mmol), and toluene (10 mL). The resulting solution was stirred for 8 h at 100° C. in an oil bath. The reaction mixture was cooled to room temperature, then was quenched by addition of 5 mL water, and extracted with DCM (3×10 mL). The organic layers were combined, washed with brine (3×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford a residue that was purified by a silica gel chromatography with ethyl acetate/pet. ether (1:3) to afford tert-butyl 4-(8-fluoro-3-nitro-2H-chromen-7-yl)piperazine-1-carboxylate as a red solid.

Step 4. Tert-Butyl 4-(3-amino-8-fluorochroman-7-yl)piperazine-1-carboxylate

Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was added tert-butyl 4-(8-fluoro-3-nitro-2H-chromen-7-yl)piperazine-1-carboxylate (150 mg, 0.39 mmol), and THF (20 mL). Borane-THF complex (4 mL, 4 mmol) was added dropwise with stirring at 0° C. To this reaction mixture was added NaBH₄ (73 mg, 1.93 mmol). The resulting solution was stirred for 12 h at 65° C., then was quenched by the addition of methanol (20 mL), and concentrated under vacuum to afford a residue that was purified by silica gel chromatography with ethyl acetate/pet. ether (0-100%) to afford tert-butyl 4-(3-amino-8-fluoro-3,4-dihydro-2H-1-benzopyran-7-yl)piperazine-1-carboxylate as yellow oil.

The following intermediate in Table 1 was prepared using standard chemical manipulations and procedures similar to those used for the preparation of Intermediate 4-1.

TABLE 1 Interme- LRMS diate Structure and Compound m/z Number Name [M + H]⁺ 4-2¹

  tert-Butyl 4-(3-amino-6- fluorochroman-7-yl)piperazine-1- carboxylate 352 ¹Notes on procedures: Step 1 was not necessary.

Intermediate 5-1. Benzyl (R)-(7-bromo-5-fluorochroman-3-yl)carbamate

Step 1. 5-Bromo-2-(bromomethyl)-1,3-difluorobenzene

A mixture of 48% HBr (130 mL, 1149 mmol) and (4-bromo-2,6-difluorophenyl)methanol (40 g, 179 mmol) was heated to reflux overnight. After cooling to room temperature, the reaction mixture was poured into 80 mL of water and was extracted with hexanes (2×300 mL). The combined organic layers were washed with sodium bicarbonate solution, dried over MgSO₄, filtered, and concentrated to afford 5-bromo-2-(bromomethyl)-1,3-difluorobenzene. ¹H NMR (CDCl₃, 300 MHz) δ (ppm): 6.94-7.22 (m, 2H), 4.46 (s, 2H).

Step 2. (2R,5S)-2-(4-bromo-2,6-difluorobenzyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine

A solution of nBuLi (6.78 mL, 10.86 mmol, 1.6 M) in hexanes was added dropwise to a solution of (S)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (2.0 g, 10.86 mmol) in 20 mL of THF at −78° C. After stirring for 30 min at −78° C., a solution of 5-bromo-2-(bromomethyl)-1,3-difluorobenzene (3.10 g, 10.86 mmol) in 10 mL of THF was added and the reaction mixture was stirred at −78° C. for 3 h. Then 20 mL of saturated NH₄C₁ solution was added. After the reaction mixture was warmed to room temperature, 150 mL of water was added and the mixture was extracted with EtOAc three times. The combined organic layers were dried over MgSO₄, filtered, and concentrated. Purification by silica gel chromatography (eluting with 0 to 15% EtOAc/Hexanes) afforded (2R,5S)-2-(4-bromo-2,6-difluorobenzyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine. ¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.03 (d, J=7.04 Hz, 2H), 4.14-4.32 (m, 1H), 3.71 (s, 3H), 3.58 (s, 3H), 3.13-3.33 (m, 1H), 2.79-2.93 (m, 1H), 2.13-2.33 (m, 1H), 1.00 (d, J=7.04 Hz, 3H), 0.64 (d, J=7.04 Hz, 3H). MS: (ESI, m/z): 389, 391 [M+H]⁺.

Step 3. Methyl (R)-2-amino-3-(4-bromo-2,6-difluorophenyl)propanoate

A solution of (2R,5S)-2-(4-bromo-2,6-difluorobenzyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (3.1 g, 8.02 mmol) in acetonitrile (60 mL) was treated with HCl (53.5 ml, 16.04 mmol, 0.3 N). The reaction mixture was stirred at room temperature for 60 min. The reaction was made basic with sat. aq. NaHCO₃ solution and the mixture was extracted with CH₂Cl₂ three times. The combined organic layers were dried over MgSO₄, filtered, and concentrated. Purification by silica gel chromatography (eluting with 0 to 100% EtOAc/Hexanes) afforded methyl (R)-2-amino-3-(4-bromo-2,6-difluorophenyl)propanoate. ¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.07 (d, J=6.74 Hz, 2H), 3.54-3.80 (m, 4H), 3.01-3.24 (m, 1H), 2.93 (s, 1H), 1.62 (br s, 2H). MS: (ESI, m/z): 294, 296 [M+H]⁺.

Step 4. (R)-2-amino-3-(4-bromo-2,6-difluorophenyl)propan-1-ol

To a solution of methyl (R)-2-amino-3-(4-bromo-2,6-difluorophenyl)propanoate (2.3 g, 7.85 mmol) in MeOH (70 mL) at room temperature was added NaBH₄ (1.043 g, 27.57 mmol) in portions. The mixture was stirred at room temperature overnight. Water was added and the MeOH was removed under reduced pressure. The aqueous mixture was extracted with choroform three times. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated to afford (R)-2-amino-3-(4-bromo-2,6-difluorophenyl)propan-1-ol. ¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.08 (d, J=6.74 Hz, 2H), 3.54-3.72 (m, 1H), 3.36 (dd, J=10.55, 7.62 Hz, 1H), 3.09 (br s, 1H), 2.51-2.86 (m, 2H), 1.74 (br s, 3H). MS: (ESI, m/z): 266, 268 [M+H]⁺.

Step 5. (R)-7-bromo-5-fluorochroman-3-amine

To a solution of (R)-2-amino-3-(4-bromo-2,6-difluorophenyl)propan-1-ol (500 mg, 1.88 mmol) in DMSO (3 mL) at room temperature was added NaH (113 mg, 2.82 mmol). The mixture was stirred at room temperature for 30 min, then at 70° C. for 30 min, and kept stirring at 50° C. overnight. After cooling to room temperature, 30 mL of water, and the mixture was extracted with EtOAc three times. The combined organic layers were washed with water, dried over Na₂SO₄, filtered, and concentrated to afford crude (R)-7-bromo-5-fluorochroman-3-amine. ¹H NMR (CDCl₃, 300 MHz) δ (ppm): 6.61-6.92 (m, 2H), 4.01-4.32 (m, 1H), 3.67-3.88 (m, 1H), 3.35 (ddt, J=7.00, 3.19, 1.80, 1.80 Hz, 1H), 2.79-3.03 (m, 1H), 2.46 (br d, J=6.74 Hz, 1H), 1.40-1.89 (m, 2H). MS: (ESI, m/z): 246, 248 [M+H]⁺.

Step 6. Benzyl (R)-(7-bromo-5-fluorochroman-3-yl)carbamate

To a solution of (R)-7-bromo-5-fluorochroman-3-amine (467 mg, 1.90 mmol) and saturated solution of sodium hydrogen carbonate (10 mL) in MeOH (20 mL) at 0° C. was added benzyl chloroformate (0.405 mL, 2.85 mmol) dropwise. The mixture was stirred overnight, allowing the temperature to warm to room temperature. 20 mL of water was added and the mixture was extracted with EtOAc three times. The combined organic layers were washed with water, dried over Na₂SO₄, filtered, and concentrated. Purification by silica gel chromatography (eluting with 7% to 60% EtOAc/Hexanes) afforded benzyl (R)-(7-bromo-5-fluorochroman-3-yl)carbamate. ¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.34 (s, 5H), 6.65-6.97 (m, 2H), 5.10 (s, 2H), 4.90-5.08 (m, 1H), 4.26 (br s, 1H), 3.97-4.21 (m, 3H), 2.89 (m, 1H), 2.78 (m, 1H). MS: (ESI, m/z): 380, 382 [M+H]⁺.

Intermediate 5-1. Benzyl (R)-(7-bromo-5-fluorochroman-3-yl)carbamate

Step 1. Diethyl 2-acetamido-2-(4-bromo-2,6-difluorobenzyl)malonate

To a stirred solution of diethyl 2-acetamidomalonate (59.2 g, 0.273 mol) in DMF (500 mL) was added t-BuOK (33.1 g, 0.295 mol) in portions at room temperature. The mixture was stirred at room temperature for 1 h and 5-bromo-2-(bromomethyl)-1,3-difluorobenzene (65.0 g, 0.227 mol) was added. The reaction mixture was stirred at room temperature for 3 h. Water (2000 mL) was added slowly and the mixture was stirred for 1 h. The resulting precipitate was collected by filtration, washed with water (3×250 mL) and dried under vacuum to give diethyl 2-acetamido-2-(4-bromo-2,6-difluorobenzyl)malonate as an off-white solid.

Step 2. 2-Acetamido-3-(4-bromo-2,6-difluorophenyl)propanoic acid

To a stirred solution of of diethyl 2-acetamido-2-(4-bromo-2,6-difluorobenzyl)malonate (80 g, 0.189 mol) in ethanol (500 mL) was added a solution of NaOH (30 g, 0.758 mol) in water (500 mL). The reaction mixture was heated at reflux for 5 h and then cooled to room temperature. The mixture was adjusted to pH=5-6 with 2N aqueous HCl and heated at reflux overnight. The mixture was cooled to room temperature and adjusted to pH=8-9 with 10% aqueous NaOH. The resulting mixture was washed with MTBE (300 mL) and the aqueous phase was adjusted to pH 2-3 with 2N aqueous HCl and then extracted with EtOAc (500 mL×2). The combined extracts were washed with brine (300 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness. The residue was treated with a mixture of EtOAc (100 mL) and pet. ether (150 mL) under stirring for 1 h. The resulting precipitate was collected by filtration, washed with pet. ether and dried under vacuum to give 2-acetamido-3-(4-bromo-2,6-difluorophenyl)propanoic acid as a white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ (ppm): 12.86 (br s, 1H), 8.31 (br s, 1H), 7.43 (d, J=6.8 Hz, 2H), 4.43 (m, 1H), 3.08-2.87 (m, 2H), 1.77 (s, 3H). MS: (ESI, m/z): 322, 324 [M+H]⁺.

Step 3. (R)-2-Acetamido-3-(4-bromo-2,6-difluorophenyl)propanoic acid

To a suspension of 2-acetamido-3-(4-bromo-2,6-difluorophenyl)propanoic acid (55 g, 0.171 mol) in distilled water (1.1 L) was added 10% aqueous NaOH dropwise to adjust pH to 8.5. The mixture was heated to 35-38° C. and L-acylase (11.0 g) was added. The reaction mixture was stirred at this temperature for 48 h while keeping the pH at 8.5 with 10% aqueous NaOH. The mixture was adjusted to pH 4-5 with 2N aqueous HCl and activated carbon (2 g) was added. The mixture was heated at 60° C. for 2 h and then cooled to room temperature. The mixture was adjusted to pH 9.5-10 with 10% aqueous NaOH and filtered. The filtrate was adjusted to pH 2-3 with 2N aqueous HCl and then extracted with EtOAc (400 mL×2). The combined extracts were washed with 0.5N aqueous HCl (200 mL×2) and brine (200 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness. The residue was treated with a mixture of EtOAc (60 mL) and pet. ether (80 mL) under stirring for 1 h. The resulting precipitate was collected by filtration, washed with pet. ether and dried under vacuum to give (R)-2-acetamido-3-(4-bromo-2,6-difluorophenyl)propanoic acid as a white solid.

Step 4. (R)-2-Amino-3-(4-bromo-2,6-difluorophenyl)propanoic acid hydrochloride

A mixture of (R)-2-acetamido-3-(4-bromo-2,6-difluorophenyl)propanoic acid (26 g, 80.7 mmol) in 6N aqueous HCl (260 mL) was heated under reflux for 5 h. The mixture was concentrated and the residue was dried under vacuum at 50° C. to provide crude (R)-2-amino-3-(4-bromo-2,6-difluorophenyl)propanoic acid hydrochloride as a white solid.

Step 5. (R)-Methyl 2-amino-3-(4-bromo-2,6-difluorophenyl)propanoate

To a solution of (R)-2-amino-3-(4-bromo-2,6-difluorophenyl)propanoic acid hydrochloride (25.4 g, 80.7 mmol) in MeOH (125 mL) was added MeOH/HCl (8M, 125 mL). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was suspended in 5% aqueous Na₂CO₃ (250 mL) and then extracted with EtOAc (250 mL×2). The combined extracts were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to give (R)-methyl 2-amino-3-(4-bromo-2,6-difluorophenyl)propanoate as an oil. ¹H NMR (CDCl₃, 400 MHz) δ (ppm): 7.08 (m, 2H), 3.73 (s, 3H), 3.70 (m, 1H), 3.09-2.87 (m, 2H), 1.55 (br s, 2H). MS: (ESI, m/z): 294, 296 [M+H]⁺.

Step 6. (R)-2-Amino-3-(4-bromo-2,6-difluorophenyl)propan-1-ol

To a stirred solution of (R)-methyl 2-amino-3-(4-bromo-2,6-difluorophenyl)propanoate (23.5 g, 79.9 mmol) in MeOH (500 mL) was added NaBH₄ (6.08 g, 159.9 mmol) portionwise. The reaction mixture was stirred at room temperature for 3 h and NaBH₄ (1.52 g, 39.9 mmol) was added. The reaction mixture was stirred at room temperature overnight. Water (500 mL) was added and MeOH was removed by evaporation under vacuum. The resulting mixture was extracted with CH₂Cl₂ (250 mL×3) and the combined extracts were dried over anhydrous Na₂SO₄, filtered, and concentrated to afford crude (R)-2-amino-3-(4-bromo-2,6-difluorophenyl)propan-1-ol as a white solid. MS: (ESI, m/z): 266, 268 [M+H]⁺.

Step 7. (R)-7-Bromo-5-fluorochroman-3-amine

To a stirred solution of (R)-2-amino-3-(4-bromo-2,6-difluorophenyl)propan-1-ol (18.5 g, 69.5 mmol) in DMSO (100 mL) was added NaH (60% in mineral oil, 4.17 g) at room temperature. The reaction mixture was stirred at 35° C. for 3 h and ice-water (500 mL) was added carefully to quench the reaction. The resulting mixture was extracted with EtOAc (300 mL×3) and the combined extracts were washed with brine (200 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to give crude (R)-7-bromo-5-fluorochroman-3-amine. MS: (ESI, m/z): 246, 248 [M+H]⁺.

Step 8. Benzyl (R)-(7-bromo-5-fluorochroman-3-yl)carbamate

To a stirred mixture of crude (R)-7-bromo-5-fluorochroman-3-amine (17 g, 69.5 mmol) and saturated aqueous NaHCO₃ (200 mL) in MeOH (400 mL) was added benzyl chloroformate (17.7 g, 104.2 mmol) dropwise. The reaction mixture was stirred at room temperature overnight and then diluted with water (500 mL). The resulting mixture was extracted with EtOAc (300 mL×2) and the combined extracts were washed with water (200 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel chromatography to give benzyl (R)-(7-bromo-5-fluorochroman-3-yl)carbamate. MS: (ESI, m/z): 380, 382 [M+H]⁺.

The following intermediate in Table 2 may be prepared using standard chemical manipulations and procedures similar to Method 2 of Intermediate 5-1.

TABLE 2 LRMS Intermediate Structure and Compound m/z Number Name [M + H]⁺ 5-2¹

  7-bromo-5-fluorochroman-4,4- d2-3-amine 248,250 ¹Notes on procedures: Step 3 and Step 8 were not performed. In Step 1, 5-bromo-2-(bromomethyl-d2)-1,3-difluorobenzene was prepared from methyl 4-bromo-2,6-difluorobenzoate in two steps: Methanol (0.806 ml, 19.92 mmol) was carefully added dropwise to a stirring solution of methyl 4-bromo-2,6-difluorobenzoate (5 g, 19.92 mmol), sodium tetrahydroborate-d4 (0.834 g, 19.92 mmol) in THF (15 mL). The reaction was then allowed to stir at 70° C. for 2 h. The reaction was cooled to room temperature and 10 mL sat. aq. NH₄Cl was added. The reaction was allowed to stir at room temperature for 2 h. The organic layer was separated. The aqueous layer was extracted with 2 × 15 mL DCM. The organic layers were combined, dried over Na₂SO₄, filtered, and concentrated under vacuum to afford (4-bromo-2,6-difluorophenyl)methan-d2-ol. A solution of (4-bromo-2,6-difluorophenyl)methan-d2-ol (3.00 g, 13.33 mmol) and PBr₃ (14.21 mL, 14.21 mmol) in DCM (30 mL) was stirred at 40° C. for 30 min. After cooling to room temperature, the reaction was quenched by the addition of water (7.5 mL). The resulting mixture was extracted with DCM (3 × 10 mL) and the organic layers were combined, dried over Na₂SO₄, filtered, and concentrated to afford a crude pale yellow oil. The oil was purified by normal phase chromatography using Biotage (KP-SIL 50 g, 2% EtOAc/hexanes up to 25% EtOAc/hexanes. Desired fractions were combined and concentrated to afford 5-bromo-2-(bromomethyl-d2)-1,3-difluorobenzene. ¹H NMR (CDCl₃, 300 MHz) δ (ppm): 1.54 (s, 1H) 4.46 (br d, J = 3.8 Hz, 1H) 7.05-7.21 (m, 2H).

Intermediate 6. tert-Butyl (R)-4-(3-amino-8-bromo-5-fluorochroman-7-yl)piperazine-1-carboxylate and

Step 1: tert-Butyl (R)-4-(3-(((benzyloxy)carbonyl)amino)-8-bromo-5-fluorochroman-7-yl)piperazine-1-carboxylate and tert-butyl (R)-4-(3-(((benzyloxy)carbonyl)amino)-6-bromo-5-fluorochroman-7-yl)piperazine-1-carboxylate

Into a 20-mL vial, was added tert-butyl 4-[(3R)-3-[[(benzyloxy)carbonyl]amino]-5-fluoro-3,4-dihydro-2H-1-benzopyran-7-yl]piperazine-1-carboxylate (570 mg, 1.17 mmol), THF (10 mL), and NBS (314 mg, 1.76 mmol). The resulting solution was stirred for 2 h at 25° C., then was quenched by the addition of water (30 mL). The resulting mixture was extracted with ethyl acetate (3×30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by prep-HPLC (Column: XSelect CSH Prep C18 OBD, 5 μm, 19×150 mm; Mobile phase A: water (0.05% TFA), B: ACN; Gradient: 45% B increasing to 70% B within 15 min). The collected fraction was concentrated under vacuum to afford tert-butyl 4-[(3R)-3-[[(benzyloxy)carbonyl]amino]-8-bromo-5-fluoro-3,4-dihydro-2H-1-benzopyran-7-yl]piperazine-1-carboxylate (peak 1) (Intermediate 6) as an off-white solid and tert-butyl 4-[(3R)-3-[[(benzyloxy)carbonyl]amino]-6-bromo-5-fluoro-3,4-dihydro-2H-1-benzopyran-7-yl]piperazine-1-carboxylate (peak 2) as off-white solid. MS (ESI, m/z): 564, 566 [M+H]⁺. These two compounds were carried on independently into subsequent synthetic steps.

Step 2: tert-Butyl 4-[(3R)-3-[[(benzyloxy)carbonyl]amino]-6-cyano-5-fluoro-3,4-dihydro-2H-1-benzopyran-7-yl]piperazine-1-carboxylate

Into a 10-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was added tert-butyl 4-[(3R)-3-[[(benzyloxy)carbonyl]amino]-6-bromo-5-fluoro-3,4-dihydro-2H-1-benzopyran-7-yl]piperazine-1-carboxylate (80 mg, 0.14 mmol), Zn(CN)₂ (13 mg, 0.11 mmol), Pd(PPh₃)₄ (8 mg, 0.01 mmol), PPh₃ (7 mg, 0.03 mmol), and NMP (5 mL). The resulting solution was stirred for 1 h at 120° C. After cooling to 25° C., the reaction was quenched by the addition of 10 mL of water. The resulting mixture was extracted with 3×20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford a residue that was purified via reverse phase chromatography (Column: C₁₈ silica gel; Mobile phase A: 0.1% TFA in H₂O, B: ACN; Flow rate: 50 mL/min; Gradient: 0% B increasing to 80% B within 30 min). The collected fractions were concentrated under vacuum to afford tert-butyl 4-[(3R)-3-[[(benzyloxy)carbonyl]amino]-6-cyano-5-fluoro-3,4-dihydro-2H-1-benzopyran-7-yl]piperazine-1-carboxylate as an off-white solid. MS (ESI, m/z): 511 [M+H]⁺.

Step 3: tert-Butyl 4-[(3R)-3-amino-6-cyano-5-fluoro-3,4-dihydro-2H-1-benzopyran-7-yl]piperazine-1-carboxylate

Into a 25-mL round-bottom flask purged and maintained with nitrogen, was placed tert-butyl 4-[(3R)-3-[[(benzyloxy)carbonyl]amino]-6-cyano-5-fluoro-3,4-dihydro-2H-1-benzopyran-7-yl]piperazine-1-carboxylate (40 mg, 0.08 mmol), ethyl acetate (4 mL), and 10% Palladium on carbon (40 mg). The resulting mixture was stirred for 2 h at 25° C. under hydrogen atmosphere. The solids were removed by filtration through Celite and the filtrate was concentrated under vacuum to afford tert-butyl 4-[(3R)-3-amino-6-cyano-5-fluoro-3,4-dihydro-2H-1-benzopyran-7-yl]piperazine-1-carboxylate (Intermediate 7-1) as yellow oil. MS (ESI, m/z): 377 [M+H]⁺.

The following intermediate in Table 3 may be prepared using standard chemical manipulations and procedures similar to those used for the preparation of Intermediate 7-1.

TABLE 3 Interme- LRMS diate Structure and Compound m/z Number Name [M + H]⁺ 7-2

  tert-butyl (R)-4-(3-amino-8- cyano-5-fluorochroman-7- yl)piperazine-1-carboxylate 377

Intermediate 8. Benzyl (6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate Intermediate 9. Benzyl (S)-(6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate and

Step 1. 6-Bromo-1,2,3,4-tetrahydronaphthalen-2-amine

A solution of 6-bromo-3,4-dihydronaphthalen-2(1H)-one (5 g, 22.21 mmol), NH₄OAc (13.8 g, 179 mmol), and NaBH₃CN (1.68 g, 26.67 mmol) in MeOH (250 mL) was stirred for 1 h at room temperature. The reaction mixture was acidified with 2N HCl solution to pH 4-5 and was concentrated under vacuum. The residual solution was washed with CH₂Cl₂ (200 mL×2). The aqueous layer was basified with 1N NaOH solution to pH 10, then extracted with CH₂Cl₂ (200 mL×2). The combined organic layer was dried over Na₂SO₄, filtered, and concentrated under vacuum to afford 6-bromo-1,2,3,4-tetrahydronaphthalen-2-amine as a yellow oil. MS: (ESI, m/z): 226, 228 [M+H]⁺.

Step 2. Benzyl (6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate (Intermediate 8)

A solution of 6-bromo-1,2,3,4-tetrahydronaphthalen-2-amine (1.8 g, 7.96 mmol), benzyl chloroformate (1.6 g, 9.55 mmol), and Cs₂CO₃ (3 g, 21.71 mmol) in THF (20 mL) and water (20 mL) was stirred at 60° C. overnight. After cooling to room temperature, the reaction mixture was extracted with EtOAc (30 mL×3). The combined organic layer was dried over Na₂SO₄, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with gradient 1:100 to 1:3 EtOAc/pet. ether) afforded benzyl (6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate (Intermediate 8) as a solid. MS: (ESI, m/z): 360, 362 [M+H]⁺.

Step 3. Benzyl (S)-(6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate (Intermediate 9) and Benzyl (R)-(6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate (Intermediate 10)

The racemate benzyl (6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate was separated by SFC (Column: Chiralpak IA-SFC-03, 5×25 cm, 5 μm; Mobile phase A: CO₂, B: MeOH; Flow rate: 170 mL/min) to afford the title compounds as follows: benzyl (S)-(6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate (first eluting isomer, RT=6.54 min) as a white solid and benzyl (R)-(6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate (second eluting isomer, RT=9.06 min) as a white solid.

First eluting isomer: ¹H NMR (CDCl₃, 400 MHz) δ (ppm): 7.30-7.21 (m, 5H), 7.17-7.13 (m, 2H), 6.85-6.83 (d, J=8.00 Hz, 1H), 5.02 (s, 2H), 4.70 (br, 1H), 3.95 (m, 1H), 3.01-2.96 (dd, J=4.00 Hz, 16.00 Hz, 2H), 2.79-2.75 (m, 2H), 2.53-2.47 (m, 1H), 2.00-1.97 (m, 1H), 1.68-1.66 (m, 1H). MS: (ESI, m/z): 360, 362 [M+H]⁺.

Second eluting isomer: ¹H NMR (CDCl₃, 400 MHz) δ (ppm): 7.30-7.23 (m, 5H), 7.17-7.13 (m, 2H), 6.84-6.82 (d, J=8.00 Hz, 1H), 5.02 (s, 2H), 4.70 (br, 1H), 4.06-3.95 (m, 1H), 3.01-2.96 (dd, J=4.00 Hz, 16.0 Hz, 2H), 2.79-2.75 (m, 2H), 2.51-2.47 (m, 1H), 2.00-1.96 (m, 1H), 1.68-1.66 (m, 1H). MS: (ESI, m/z): 360, 362 [M+H]⁺.

Step 1. 2-(4-Bromo-2-fluorophenyl)acetyl chloride

A 250-mL round-bottom flask was charged with 2-(4-bromo-2-fluorophenyl)acetic acid (10 g, 42.05 mmol), DCM (50 mL), and thionyl chloride (6.3 mL, 85.11 mmol). The resulting solution was stirred for 16 h at 40° C. After cooling to 25° C., the reaction mixture was concentrated under vacuum to afford 2-(4-bromo-2-fluorophenyl)acetyl chloride as brown oil.

Step 2. 6-Bromo-8-fluoro-3,4-dihydronaphthalen-2(1H)-one

A 500-mL round-bottom flask was charged with 2-(4-bromo-2-fluorophenyl)acetyl chloride (5.0 g, 18.49 mmol) and DCM (100 mL). AlCl₃ (7.15 g, 53.09 mmol) was then added in portions at 0° C. The resulting mixture was stirred for 10 min at 0° C., then a gentle stream of ethylene gas was bubble into the reaction mixture for 5 h at 0° C. The reaction mixture was poured into ice and concentrated hydrochloric acid (5 mL) was added. The resulting solution was extracted with DCM (3×50 mL), the organic layers combined, dried over anhydrous sodium sulfate and concentrated under vacuum to afford a crude residue that was purified by column chromatography eluting with ethyl acetate/pet. ether (1:2) to afford 6-bromo-8-fluoro-3,4-dihydronaphthalen-2(1H)-one as a brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 2.49 (t, J=8.0 Hz, 2H), 3.08 (t, J=8.0 Hz, 2H), 3.49 (s, 2H), 7.40-7.42 (m, 2H).

Step 3. (2E)-6-Bromo-8-fluoro-N-methoxy-1,2,3,4-tetrahydronaphthalen-2-imine

A 250-mL round-bottom flask was charged with 6-bromo-8-fluoro-3,4-dihydronaphthalen-2(1H)-one (4.2 g, 16.07 mmol), the HCl salt of O-methylhydroxylamine (2.16 g, 25.60 mmol), ethanol (50 mL) and pyridine (5 mL, 61.50 mmol). The resulting mixture was stirred for 16 h at 80° C. in an oil bath, then was cooled to 25° C. After cooling, the resulting mixture was concentrated under vacuum to afford a residue that was purified by column chromatography eluting with ethyl acetate/pet. ether (1:2) to afford (2E)-6-bromo-8-fluoro-N-methoxy-1,2,3,4-tetrahydronaphthalen-2-imine as a brown solid. MS: (ESI, m/z) 272, 274 [M+H]⁺.

Step 4. 6-Bromo-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-amine

A 250-mL round-bottom flask that was purged with nitrogen was charged with (2E)-6-bromo-8-fluoro-N-methoxy-1,2,3,4-tetrahydronaphthalen-2-imine (3.5 g, 11.58 mmol, 90%), ethanol (50 mL) and Raney Ni (2.0 g, 23.11 mmol). To this hydrogen (g) was introduced in. The resulting mixture was stirred for 48 h at 25° C. The solids were removed by filtration over Celite. The filtrate was concentrated under vacuum to afforad a residue that was purified by column chromatography eluting with DCM/methanol (10:1) to afford 6-bromo-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-amine as a brown solid. MS: (ESI, m/z): 244, 246 [M+H]⁺.

Step 5. Benzyl (6-bromo-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate

A 100-mL round-bottom flask was charged with 6-bromo-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-amine (930 mg, 3.43 mmol), ethyl acetate (15 mL), water (15 mL), potassium carbonate (1.58 g, 11.32 mmol), and benzyl chloroformate (780 mg, 4.53 mmol). The resulting mixture was stirred for 16 h at 60° C. in an oil bath. After cooling to 25° C., the reaction was diluted with water (30 mL). The resulting solution was extracted with ethyl acetate (3×40 mL), the organic layers combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford a residue that was purified by column chromatography eluting with ethyl acetate/pet. ether (1:5) to afford benzyl (6-bromo-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate as an off-white solid. MS: (ESI, m/z): 378, 380 [M+H]⁺.

The following intermediates in Table 4 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Intermediate 11-1.

TABLE 4 LRMS Intermediate m/z Number Structure and Compound Name [M + H]⁺ 11-2¹

  benzyl (S)-(6-bromo-7-methyl- 1,2,3,4-tetrahydronaphthalen-2- yl)carbamate 374, 376 11-3¹

  benzyl (R)-(6-bromo-7-methyl- 1,2,3,4-tetrahydronaphthalen-2- yl)carbamate 374, 376 11-4¹

  benzyl (S)-(6-bromo-5-methyl- 1,2,3,4-tetrahydronaphthalen-2- yl)carbamate 374, 376 11-5¹

  benzyl (R)-(6-bromo-5-methyl- 1,2,3 ,4-tetrahydronaphthalen-2- yl)carbamate 374, 376 ¹Notes on procedures: In Step 2, a mixture of regioisomers 6-bromo-7-methyl-3,4-dihydronaphthalen-2(1H)-one and 6-bromo-5-methyl-3,4-dihydronaphthalen-2(1H)-one (3:1, respectively) were generated. The mixture was carried through Step 5. The regioisomers and enantiomers were separated by SFC using the chiral column Phenomenex Lux 5 μm Cellulose-3 and mobile phase 50% CO₂/IPA (2 mM NH₃-MeOH) to provide Intermediate 11-4 as the first eluting isomer, Intermediate 11-2 as the second eluting isomer, Intermediate 11-5 as the third eluting isomer, and Intermediate 11-3 as the fourth eluting isomer. Stereochemistry of the separated enantiomers were arbitrarily assigned.

Step 1. 7-Bromo-2H-chromene-3-carbonitrile

A solution of 4-bromo-2-hydroxybenzaldehyde (10 g, 47.26 mmol) and triethylenediamine (1.12 g, 9.49 mmol) in acrylonitrile (16 mL) was stirred for 24 h at 80° C. After cooling to room temperature, the reaction was quenched with 1N NaOH (400 mL). The resulting solution was extracted with EtOAc (300 mL×3). The organic layers were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 20:1-9:1 pet. ether/EtOAc) to give 7-bromo-2H-chromene-3-carbonitrile as a yellow solid. MS: (ESI, m/z): 236, 238 [M+H]⁺.

Step 2. Tert-Butyl 4-(3-cyano-2H-chromen-7-yl)piperazine-1-carboxylate

A mixture of 7-bromo-2H-chromene-3-carbonitrile (1 g, 3.81 mmol), tert-butyl piperazine-1-carboxylate (950 mg, 4.85 mmol), Pd(dppf)Cl₂ (327 mg, 0.42 mmol), XPhos (191 mg, 0.38 mmol) and Cs₂CO₃ (3.9 g, 11.37 mmol) in toluene (20 mL) was stirred for 18 h at 100° C. After cooling to room temperature, the reaction was quenched by the addition of 30 mL of water. The resulting mixture was extracted with EtOAc (30 mL×3). The organic layers were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 9:1-4:1 pet. ether/EtOAc) to give 0.7 g of tert-butyl 4-(3-cyano-2H-chromen-7-yl)piperazine-1-carboxylate as a yellow solid. MS: (ESI, m/z): 342 [M+H]⁺.

Step 3. Tert-Butyl 4-(3-carbamoyl-2H-chromen-7-yl)piperazine-1-carboxylate

A solution of tert-butyl 4-(3-cyano-2H-chromen-7-yl)piperazine-1-carboxylate (500 mg, 1.32 mmol), 30% hydrogen peroxide (0.2 mL, 2.58 mmol), and potassium carbonate (304 mg, 2.09 mmol) in a mixture of DMSO (2 mL) and ethanol (10 mL) was stirred for 3 h at room temperature. The reaction was quenched by the addition of 50 mL of water. The resulting mixture was extracted with EtOAc (50 mL×3). The organic layers were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 10:1-3:1 pet. ether/EtOAc) to give tert-butyl 4-(3-carbamoyl-2H-chromen-7-yl)piperazine-1-carboxylate as a yellow solid. MS: (ESI, m/z): 360 [M+H]⁺.

Step 4. Tert-Butyl 4-(3-carbamoylchroman-7-yl)piperazine-1-carboxylate

A mixture of tert-butyl 4-(3-carbamoyl-2H-chromen-7-yl)piperazine-1-carboxylate (700 mg, 1.95 mmol) and Pd/C (100 mg, 10%) in THF (50 mL) was stirred for 18 h at room temperature under an atmosphere of hydrogen. The solids were filtered away and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with EtOAc) to give tert-butyl 4-(3-carbamoylchroman-7-yl)piperazine-1-carboxylate as a light yellow solid. MS: (ESI, m/z): 362 [M+H]⁺.

Step 5. Tert-Butyl 4-(3-aminochroman-7-yl)piperazine-1-carboxylate

To a stirring solution of (diacetoxyiodo)benzene (468 mg, 1.45 mmol) in a mixture of DMF (3.88 mL) and water (3.88 mL) was added tert-butyl 4-(3-carbamoylchroman-7-yl)piperazine-1-carboxylate (350 mg, 0.97 mmol). The resulting solution was stirred for 18 h at room temperature. Additional (diacetoxyiodo)benzene (936 mg, 2.90 mmol) was added in two portions over 24 h. The resulting solution was diluted with 20 mL of water and was extracted with EtOAc (50 mL). The aqueous layer was concentrated under vacuum. The residue was purified by prep-HPLC (Column: SunFire Prep C₁₈, 19×150 mm; Mobile phase A: water (0.05% NH₄HCO₃), B: ACN; Gradient: 15% B to 70% B in 15 min) to afford tert-butyl 4-(3-aminochroman-7-yl)piperazine-1-carboxylate as a light yellow solid. MS: (ESI, m/z): 334 [M+H]⁺.

Step 1. 7-Chlorochroman-3-amine

A solution of 7-chlorochroman-3-one (700 mg, 3.83 mmol) and NH₄OAc (2.37 g, 30.75 mmol) in MeOH (35 mL) was stirred for 4 h at room temperature. To this was added NaBH₃CN (364 mg, 5.79 mmol). The resulting mixture was stirred for 14 h at room temperature and then concentrated under vacuum. The residue was diluted with 50 mL of water. The pH value of the mixture was adjusted to 5 with 1N HCl. The resulting mixture was extracted with CH₂Cl₂ (20 mL×2). The pH value of the aqueous layer was adjusted to 10 with 1M NaOH solution. The resulting solution was extracted with CH₂Cl₂ (30 mL×3). The organic layers were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to afford 7-chlorochroman-3-amine as a light yellow oil. MS: (ESI, m/z): 184 [M+H]⁺.

Step 2. Benzyl (7-chlorochroman-3-yl)carbamate

A mixture of 7-chlorochroman-3-amine (350 mg, 1.91 mmol), potassium carbonate (786.6 mg, 5.69 mmol), and benzyl chloroformate (390 mg, 2.29 mmol) in a mixture of EtOAc (15 mL) and water (15 mL) was stirred for 3 h at 60° C. After cooling to room temperature, the reaction mixture was poured into 10 mL of water and was extracted with EtOAc (10 mL×3). The organic layers were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 7:1 pet. ether/EtOAc) to afford benzyl (7-chlorochroman-3-yl)carbamate as a white solid. MS: (ESI, m/z): 318 [M+H]⁺.

Step 3. Tert-Butyl 3-(3-(((benzyloxy)carbonyl)amino)chroman-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Into a 20-mL sealed tube purged and maintained with an inert atmosphere of nitrogen was placed benzyl (7-chlorochroman-3-yl)carbamate (95 mg, 0.26 mmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70 mg, 0.33 mmol), Cs₂CO₃ (294 mg, 0.90 mmol), toluene (5 mL) and RuPhos Pd G3 (25.1 mg, 0.03 mmol). The reaction mixture was treated with microwave radiation for 5 h at 120° C. After cooling to room temperature, the reaction mixture was then poured into 10 mL of water. The resulting mixture was extracted with CH₂Cl₂ (10 mL×3). The organic layers were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 2:1 pet. ether/EtOAc) to afford tert-butyl 3-(3-(((benzyloxy)carbonyl)amino)chroman-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as light yellow oil. MS: (ESI, m/z): 494 [M+H]⁺.

Step 4. Tert-Butyl 3-(3-aminochroman-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

A mixture of tert-butyl 3-(3-(((benzyloxy)carbonyl)amino)chroman-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.60 mmol) and Pd/C (60 mg, 10%) in MeOH (25 mL) was stirred for 2 h at room temperature under an atmosphere of hydrogen. The solids were filtered away and the filtrate was concentrated to give tert-butyl 3-(3-aminochroman-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow oil. MS: (ESI, m/z): 360 [M+H]⁺.

Step 1. Tert-Butyl 3-(3-(((benzyloxy)carbonyl)amino)chroman-7-yl)-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate

A mixture of benzyl-(7-bromochroman-3-yl)carbamate, Intermediate 1, (400 mg, 1.07 mmol), tert-butyl 3,9-diazabicyclo[3.3.1]nonane-9-carboxylate (300 mg, 1.31 mmol), Pd(dppf)Cl₂—CH₂Cl₂ (90 mg, 0.11 mmol), Xphos (52 mg, 0.11 mmol), and Cs₂CO₃ (722 mg, 2.22 mmol) in toluene (6 mL) was stirred at 100° C. for 14 h. After cooling to room temperature, water was added and the reaction mixture was extracted with EtOAc (70 mL×2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. Purification by prep-TLC (eluting with 1:3 EtOAc/pet. ether) afforded tert-butyl 3-(3-(((benzyloxy)carbonyl)amino)chroman-7-yl)-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate as a pale yellow solid. MS: (ESI, m/z): 508 [M+H]⁺.

Step 2. Tert-Butyl 3-(3-(((benzyloxy)carbonyl)amino)chroman-7-yl)-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate

A mixture of tert-butyl 3-(3-(((benzyloxy)carbonyl)amino)chroman-7-yl)-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate (120 mg, 0.22 mmol) and Pd/C (60 mg, 10%) in MeOH (5 mL) was stirred for 1 h at room temperature under an atmosphere of hydrogen. The solids were filtered away and the filtrate was concentrated under vacuum to afford tert-butyl 3-(3-(((benzyloxy)carbonyl)amino)chroman-7-yl)-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate as colorless oil. MS: (ESI, m/z): 374 [M+H]⁺.

The following intermediate in Table 5 was prepared using standard chemical manipulations and procedures similar to those used for the preparation of Intermediate 14-1.

TABLE 5 Interme- LRMS diate m/z Number Structure and Name [M + H]⁺ 14-2

  tert-butyl 4-(3-aminochroman-7- yl)-2,3-dimethylpiperazine-1- carboxylate 362 ¹Notes on Procedures: In Step 1, RuPhos Pd G3/RuPhos was used as the catalyst/ligand system.

Step 1. 2,4-Difluoro-6-hydroxybenzaldehyde

A solution of 3,5-difluorophenol (10 g, 73 mmol), paraformaldehyde (23 g, 728 mmol), Et₃N (21 mL), and MgCl₂ (14.6 g, 153.34 mmol) in ACN (200 mL) was stirred for 14 h at 60° C. After cooling to room temperature, the reaction was quenched by the addition of water (100 mL). The resulting mixture was extracted with DCM (2×200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography (eluting with gradient 1:10 to 1:1 EtOAc/pet. ether) afforded 2,4-difluoro-6-hydroxybenzaldehyde as a pale yellow solid. MS: (ESI, m/z): 159 [M+H]⁺.

Step 2. Tert-Butyl 3-(3-fluoro-4-formyl-5-hydroxyphenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

A solution of 2,4-difluoro-6-hydroxybenzaldehyde (600 mg, 3.80 mmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (800 mg, 3.75 mmol), and DIEA (700 mg, 5.42 mmol) in DMSO (10 mL) was stirred for 2 h at 100° C. After cooling to room temperature the reaction was quenched by the addition of water (10 mL). The resulting mixture was extracted with DCM (2×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:4 EtOAc/pet. ether) afforded tert-butyl 3-(3-fluoro-4-formyl-5-hydroxyphenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. MS: (ESI, m/z): 351 [M+H]⁺.

Step 3. Tert-Butyl 3-(3-(allyloxy)-5-fluoro-4-formylphenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

A solution of tert-butyl 3-(3-fluoro-4-formyl-5-hydroxyphenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.4 g, 3.60 mmol), potassium carbonate (3 g, 21.71 mmol), and allylbromide (500 mg, 4.13 mmol) in DMF (20 mL) was stirred for 2 h at 100° C. After cooling to room temperature the reaction was quenched by the addition of water (20 mL). The resulting mixture was extracted with DCM (2×50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:5 EtOAc/pet. ether) afforded tert-butyl 3-(3-(allyloxy)-5-fluoro-4-formylphenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. MS: (ESI, m/z): 392 [M+H]⁺.

Step 4. Tert-Butyl 3-(3-(allyloxy)-5-fluoro-4-vinylphenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

To a solution of methyltriphenylphosphonium bromide (3.3 g, 8.86 mmol) in THF (25 mL) was added sodium hydride (178 mg, 4.45 mmol, 60% dispersion in oil) in portions at 0° C. The reaction mixture was stirred for 4 h at room temperature. This was followed by the dropwise addition of a solution of tert-Butyl 3-(3-(allyloxy)-5-fluoro-4-formylphenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.2 g, 2.77 mmol) in THF (20 mL) and stirring continued for 3 h at 30° C. The reaction was quenched by the addition of water (60 mL). The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with gradient 1:6 to 1:1 EtOAc/pet. ether) afforded tert-butyl 3-(3-(allyloxy)-5-fluoro-4-vinylphenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a colorless oil. MS: (ESI, m/z): 389 [M+H]⁺.

Step 5. Tert-Butyl 3-(5-fluoro-2H-chromen-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

A solution of tert-butyl 3-(3-(allyloxy)-5-fluoro-4-vinylphenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (800 mg, 2.06 mmol) and Grubbs Catalyst™ 2^(nd) Gen (48 mg, 0.05 mmol) in DCM (10 mL) was stirred for 1 h at room temperature. The mixture was concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:3 EtOAc/pet. ether) afforded tert-butyl 3-(5-fluoro-2H-chromen-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a colorless oil. MS: (ESI, m/z): 361 [M+H]⁺.

Step 6. Tert-Butyl 3-(5-fluoro-3-nitro-2H-chromen-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

A solution of KNO₂ (945 mg, 11.10 mmol) and 18-crown-6 (2.2 g, 8.32 mmol) in THF (20 mL) was stirred for 1 h at room temperature. Then 12 (2.3 g, 9.06 mmol) was added and stirring was continued for 1 h. Finally, a solution of tert-butyl 3-(5-fluoro-2H-chromen-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1 g, 2.77 mmol) and pyridine (110 mg, 1.39 mmol) in THF (10 mL) was added to the solution and stirring was continued for 14 h. The reaction was quenched by the addition of water (20 mL). The resulting mixture was extracted with DCM (2×50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:6 EtOAc/pet. ether) afforded tert-butyl 3-(5-fluoro-3-nitro-2H-chromen-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. MS: (ESI, m/z): 406 [M+H]⁺.

Step 7. Tert-Butyl 3-(3-amino-5-fluorochroman-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

A solution of tert-butyl 3-(5-fluoro-3-nitro-2H-chromen-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 0.30 mmol), BH₃-THF (1 M, 20 mL, 20.0 mmol), and NaBH₄ (116 mg, 3.07 mmol) in THF (20 mL) was stirred for 14 h at 65° C. Then methanol (20 mL) was added and stirring was continued for 4 h at 85° C. The mixture was concentrated under vacuum. Purification by reverse phase chromatography (Column: C₁₈ silica gel; Mobile phase A: water with 10 mM NH₄HCO₃, B: ACN; Flow rate: 50 mL/min; Gradient: 0% to 50% B over 40 min) gave tert-butyl 3-(3-amino-5-fluorochroman-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a colorless oil. MS: (ESI, m/z): 378 [M+H]⁺.

The following intermediates in Table 6 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Intermediate 15-1.

TABLE 6 Interme- LRMS diate m/z Number Structure and Name [M + H]⁺ 15-2¹

  tert-butyl 4-(3-amino-6- (trifluoromethoxy)chroman-7- yl)piperazine-1-carboxylate 418 15-3

  tert-butyl 4-(3-amino-5- fluorochroman-7-yl)piperazine-1- carboxylate 352 15-4

  tert-butyl 3-(3-amino-5- fluorochroman-7-yl)-3,6- diazabicyclo[3.1.1]heptane-6- carboxylate 364 ¹Notes on procedures: Step 6: nitration was conducted by sonicating a solution of tert-butyl 4-[6-(trifluoromethoxy)-2H-chromen-7-yl]piperazine-1-carboxylate (800 mg, 2.00 mmol), ACN (2.2 g, 4.00 mmol), NaNO₂ (1.4 g, 20.29 mmol) and acetic acid (1.44 g, 23.98 mmol) in chloroform (40 mL) for 6 h at 50° C. The reaction was quenched with sat. aq. NaHCO₃ solution (40 mL) and an extractive work up was performed with EtOAc.

Step 1. 2-Chloro-5-fluoro-6-methylnicotinonitrile

A mixture of 2,6-dichloro-5-fluoropyridine-3-carbonitrile (5 g, 26.18 mmol), methylboronic acid (1.58 g, 26.36 mmol), Na₂CO₃ (8.33 g, 78.54 mmol), and Pd(dppf)Cl₂—CH₂Cl₂ (958 mg, 1.31 mmol) in DMF (40 mL) and water (20 mL) was stirred for 3 h at 80° C. After cooling to room temperature, the reaction mixture was diluted with 50 mL of water. The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:5 EtOAc/pet. ether) afforded 2-chloro-5-fluoro-6-methylnicotinonitrile as a pink solid. MS: (ESI, m/z): 171 [M+H]⁺.

Step 2. Methyl 3-amino-5-fluoro-6-methylthieno[2,3-b]pyridine-2-carboxylate

A solution of 2-chloro-5-fluoro-6-methylnicotinonitrile (1.40 g, 8.21 mmol), KOH (1.38 g, 24.63 mmol), and methyl 2-mercaptoacetate (1.74 g, 16.42 mmol) in DMF (20 mL) and water (20 mL) was stirred for 3 h at room temperature. The pH value of the solution was adjusted to 5 with 1N HCl solution. The solids were collected by filtration to afford methyl 3-amino-5-fluoro-6-methylthieno[2,3-b]pyridine-2-carboxylate as a yellow solid. MS: (ESI, m/z): 241 [M+H]⁺.

Step 3. 3-Amino-5-fluoro-6-methylthieno[2,3-b]pyridine-2-carboxylic Acid

A solution of methyl 3-amino-5-fluoro-6-methylthieno[2,3-b]pyridine-2-carboxylate (200 mg, 0.83 mmol) and NaOH (66 mg, 1.66 mmol) in MeOH (2 mL) and water (1 mL) was stirred for 1 h at 60° C. After cooling to room temperature, the resulting mixture was concentrated under vacuum. The residue was diluted with 20 mL of water. The pH value of the mixture was adjusted to 5 with 1N HCl solution. The solids were collected by filtration to give 3-amino-5-fluoro-6-methylthieno[2,3-b]pyridine-2-carboxylic acid as a yellow solid. MS: (ESI, m/z): 227 [M+H]⁺.

Step 1. Methyl 3-amino-5-fluorothieno[2,3-b]pyridine-2-carboxylate

Sodium (230 mg, 10.00 mmol) was added to MeOH (20 mL) at 0° C. and the resulting mixture was stirred for 30 min at 0° C. until the sodium was consumed. To the reaction mixture was added 2-chloro-5-fluoronicotinonitrile (900 mg, 5.75 mmol) and methyl 2-mercaptoacetate (1.8 mL, 14.98 mmol). The resulting solution was stirred for 16 h at room temperature. The reaction was quenched by the addition of 50 mL of water and was extracted with DCM (3×50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:1 EtOAc/pet. ether) afforded methyl 3-amino-5-fluorothieno[2,3-b]pyridine-2-carboxylate as a yellow solid. MS: (ESI, m/z): 227 [M+H]⁺.

Step 2. 3-Amino-5-fluorothieno[2,3-b]pyridine-2-carboxylic Acid

A solution of methyl 3-amino-5-fluorothieno[2,3-b]pyridine-2-carboxylate (1 g, 3.76 mmol) and LiOH (100 mg, 3.97 mmol) in water (10 mL) and dioxane (10 mL) was stirred for 1 h at room temperature. The reaction was diluted with 20 mL of water and was extracted with EtOAc (3×30 mL). The pH value of the aqueous layer was adjusted to 6 with 6N HCl solution. The solids were collected by filtration to afford 3-amino-5-fluorothieno[2,3-b]pyridine-2-carboxylic acid as a yellow solid. MS: (ESI, m/z): 213 [M+H]⁺.

Step 1. 2,6-Difluoronicotinonitrile

A mixture of 2,6-dichloronicotinonitrile (6.92 g, 40.00 mmol) and KF (6.98 g, 120.14 mmol) in DMF (30 mL) was stirred overnight at 90° C. After cooling to room temperature, the reaction was quenched by the addition of 100 mL of water. The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatograpy (eluting with 1:3 EtOAc/pet. ether) afforded 2,6-difluoronicotinonitrile as a white solid. MS: (ESI, m/z): 141 [M+H]⁺.

Step 2. Benzyl 2-((3-cyano-6-fluoropyridin-2-yl)thio)acetate

To a mixture of 2,6-difluoronicotinonitrile (1 g, 6.42 mmol) and NaOAc (878 mg, 10.70 mmol) in THF (20 mL) was added benzyl 2-mercaptoacetate (1.17 g, 6.42 mmol) at −70° C. The resulting solution was warmed to room temperature slowly and then stirred for 30 min. The reaction was quenched by the addition of 20 mL of water. The resulting mixture was extracted with DCM (3×30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography (eluting with 2:25 EtOAc/pet. ether) afforded benzyl 2-((3-cyano-6-fluoropyridin-2-yl)thio)acetate as a white solid. MS: (ESI, m/z): 303 [M+H]⁺.

Step 3. Benzyl 3-amino-6-fluorothieno[2,3-b]pyridine-2-carboxylate

A solution of benzyl 2-((3-cyano-6-fluoropyridin-2-yl)thio)acetate (120 mg, 0.40 mmol) in THF (2 mL) was added dropwise at −50° C. to a solution of DBU (120 mg, 0.79 mmol) in THF (3 mL). The mixture was then warmed to room temperature and stirred overnight. The resulting solution was concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:1 EtOAc/pet. ether) afforded benzyl 3-amino-6-fluorothieno[2,3-b]pyridine-2-carboxylate as an off-white solid. MS: (ESI, m/z): 303 [M+H]⁺.

Step 4. 3-Amino-6-fluorothieno[2,3-b]pyridine-2-carboxylic Acid

A mixture of benzyl 3-amino-6-fluorothieno[2,3-b]pyridine-2-carboxylate (89 mg, 0.29 mmol) and Pd/C (20 mg, 10%) in EtOAc (15 mL) was was stirred for 1 h at room temperature. The solids were filtered out. The filtrate was concentrated under vacuum to give 3-amino-6-fluorothieno[2,3-b]pyridine-2-carboxylic acid as a light yellow solid. MS: (ESI, m/z): 213 [M+H]⁺.

Step 1. 2-Chloro-6-methoxynicotinonitrile

Sodium (1.5 g, 65.22 mmol) was added to MeOH (25 mL) at 0° C. and the resulting mixture was stirred for 30 min at room temperature until the sodium was consumed. To the reaction mixture was added 2,6-dichloronicotinonitrile (5 g, 28.90 mmol) over 5 min, maintaining reaction temperature below 10° C. The resulting solution was stirred overnight at room temperature. The solids were filtered away and the filtrate was concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:3 EtOAc/hexanes) afforded 2-chloro-6-methoxynicotinonitrile as a white solid. MS: (ESI, m/z): 169 [M+H]⁺.

Step 2. Methyl 3-amino-6-methoxythieno[2,3-b]pyridine-2-carboxylate

To a solution of 2-chloro-6-methoxynicotinonitrile (3.9 g, 23.13 mmol) in DMF (10 mL) was added KOH (5.2 g) at 0° C. over 5 min, followed by the addition of methyl 2-mercaptoacetate (2.46 g, 23.18 mmol). The resulting solution was stirred for 1 h at 0° C. The reaction was quenched by the addition of 20 mL of water. The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:10 to 1:1 EtOAc/hexanes) afforded methyl 3-amino-6-methoxythieno[2,3-b]pyridine-2-carboxylate as a light yellow solid. 1H NMR (DMSO-d₆, 300 MHz) δ (ppm): 8.40 (d, J=8.7 Hz, 1H), 7.24 (br, 2H), 6.89 (d, J=9.0 Hz, 1H), 3.93 (s, 3H), 3.77 (s, 3H). MS: (ESI, m/z): 239 [M+H]⁺.

Step 3. 3-Amino-6-methoxythieno[2,3-b]pyridine-2-carboxylic Acid

A solution of methyl 3-amino-6-methoxythieno[2,3-b]pyridine-2-carboxylate (110 mg, 0.46 mmol) and LiOH (100 mg, 4.18 mmol) in THF (4 mL) and water (1.5 mL) was stirred for 2 h at 60° C. After cooling to room temperature, the resulting mixture was concentrated under vacuum. The residue was diluted with 2 mL of water. The pH value of the solution was adjusted to 7 with 1N HCl. The solids were collected by filtration to afford 3-amino-6-methoxythieno[2,3-b]pyridine-2-carboxylic acid as a yellow solid. MS: (ESI, m/z): 225 [M+H]⁺.

Step 1. 2-Chloro-5-fluoro-6-methoxynicotinonitrile

A mixture of 2,6-dichloro-5-fluoropyridine-3-carbonitrile (3.0 g, 15.71 mmol) and MeONa (1.28 g, 23.70 mmol) in MeOH (30 mL) was stirred for 5 h at room temperature. The resulting mixture was concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:3 EtOAc/pet. ether) afforded 2-chloro-5-fluoro-6-methoxynicotinonitrile as a yellow solid. MS: (ESI, m/z): 187, 189 [M+H]⁺.

Step 2. Methyl 3-amino-5-fluoro-6-methoxythieno[2,3-b]pyridine-2-carboxylate

A solution of 2-chloro-5-fluoro-6-methoxynicotinonitrile (1.90 g, 10.22 mmol) methyl 2-mercaptoacetate (1.3 g, 12.26 mmol), and DBU (7.2 g, 47.29 mmol) in THF (30 mL) was stirred overnight at room temperature. The reaction was quenched by the addition of 50 mL of water and was extracted with EtOAc (3×50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:3 EtOAc/pet. ether) afforded methyl 3-amino-5-fluoro-6-methoxythieno[2,3-b]pyridine-2-carboxylate as a yellow solid. MS: (ESI, m/z): 257 [M+H]⁺.

Step 3. 3-Amino-5-fluoro-6-methoxythieno[2,3-b]pyridine-2-carboxylic Acid

A mixture of methyl 3-amino-5-fluoro-6-methoxythieno[2,3-b]pyridine-2-carboxylate (500 mg, 1.95 mmol) and LiOH (236 mg, 9.85 mmol) in THF (8 mL) and water (8 mL) was stirred overnight at 60° C. After cooling to room temperature, the solvent was removed under vacuum. The pH value of the residue was adjusted to 7 with 3N HCl. The solids were collected by filtration to afford 3-amino-5-fluoro-6-methoxythieno[2,3-b]pyridine-2-carboxylic acid as a yellow solid. MS: (ESI, m/z): 243 [M+H]⁺.

Step 1. Methyl 3-amino-4,6-dimethylthieno[2,3-b]pyridine-2-carboxylate

To a solution of 2-chloro-4,6-dimethylnicotinonitrile (2.000 g, 12.00 mmol) and DBU (5.00 g, 32.84 mmol) in DMF (20 mL) was added methyl 2-sulfanylacetate (1.019 g, 9.60 mmol) dropwise with stirring at −50° C. The resulting solution was stirred overnight at room temperature. The mixture was poured into water (50 mL) and the solids were collected by filtration to give methyl 3-amino-4,6-dimethylthieno[2,3-b]pyridine-2-carboxylate as a light yellow solid. MS: (ESI, m/z): 237 [M+H]⁺.

Step 2. 3-Amino-4,6-dimethylthieno[2,3-b]pyridine-2-carboxylic Acid

To a solution of methyl 3-amino-4,6-dimethylthieno[2,3-b]pyridine-2-carboxylate (300 mg, 1.27 mmol) in MeOH (5 mL) was added a solution of NaOH (254 mg, 6.35 mmol) in water (5 mL). The resulting solution was stirred for 3 h at 70° C. After cooling to room temperature, the solvent was removed under vacuum. The pH value of the residue was adjusted to 6 with 3N HCl. The solids were collected by filtration to afford 3-amino-4,6-dimethylthieno[2,3-b]pyridine-2-carboxylic acid as a yellow solid. MS: (ESI, m/z): 223 [M+H]⁺.

Step 1. 6-Methyl-2-thioxo-4-(trifluoromethyl)-1,2-dihydropyridine-3-carbonitrile

A solution of 2-cyanoethanethioamide (2 g, 19.97 mmo) 1,1,1-trifluoropentane-2,4-dione (3 g, 19.47 mmol), and triethylamine (0.1 mL) in in ethanol (20 mL) was stirred for 1 h at 90° C. After cooling to room temperature, the solids were collected by filtration and dried in an oven under reduced pressure to afford 6-methyl-2-thioxo-4-(trifluoromethyl)-1,2-dihydropyridine-3-carbonitrile as a yellow solid. MS: (ESI, m/z): 219 [M+H]⁺.

Step 2. Ethyl 3-amino-6-methyl-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxylate

A solution of 6-methyl-2-thioxo-4-(trifluoromethyl)-1,2-dihydropyridine-3-carbonitrile (800 mg, 3.67 mmol), ethyl 2-bromoacetate (609 mg, 3.65 mmol), and NaOEt (297 mg, 4.37 mmol) in ethanol (20 mL) was stirred overnight at 80° C. The solvent was removed under vacuum. The residue was diluted with 30 mL of water and was extracted with ethyl acetate (3×30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:10 to 1:1 EtOAc/pet. ether) afforded ethyl 3-amino-6-methyl-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxylate as a yellow solid. MS: (ESI, m/z): 305 [M+H]⁺.

Step 3. 3-Amino-6-methyl-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxylic Acid

A solution of ethyl 3-amino-6-methyl-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxylate (1.0 g, 3.29 mmol) and sodium hydroxide (470 mg, 11.75 mmol) in water (2 mL) and methanol (10 mL) was stirred for 2 h at 60° C. The resulting mixture was concentrated under vacuum. The residue was diluted with 10 mL of water. The pH value of the solution was adjusted to 3 with 3N HCl. The solids were collected by filtration to give 3-amino-6-methyl-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxylic acid as a yellow solid. MS: (ESI, m/z): 277 [M+H]⁺.

Intermediate 23. Methyl 6-amino-2-methylthieno[2,3-d]thiazole-5-carboxylate and

Step 1. 4-Chloro-2-methylthiazole-5-carbonitrile

A mixture of 2,4-dichlorothiazole-5-carbonitrile (1.00 g, 5.59 mmol), dimethylzinc (1M in Et₂O) (8.8 mL, 8.80 mmol), and Pd(dppf)Cl₂ ⁻CH₂Cl₂ (911 mg, 1.12 mmol) in toluene (30 mL) was stirred for 4 h at 40° C. The reaction was quenched by the addition of 20 mL of water. The resulting mixture was extracted with EtOAc (3×20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:5 EtOAc/pet. ether) afforded 4-chloro-2-methylthiazole-5-carbonitrile as a light yellow solid. MS: (ESI, m/z): 159 [M+H]⁺.

Step 2. Methyl 6-amino-2-methylthieno[2,3-d]thiazole-5-carboxylate

To a solution of 4-chloro-2-methylthiazole-5-carbonitrile (550 mg, 3.47 mmol) and DBU (1.06 g, 6.94 mmol) in THF (20 mL) was added a solution of methyl 2-mercaptoacetate (443 mg, 4.17 mmol) in THF (2 mL) dropwise with stirring at −40° C. The resulting solution allowed to warm to to room temperature while stirring overnight. The reaction was quenched with 20 mL of water. The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:7 EtOAc/pet. ether) afforded methyl 6-amino-2-methylthieno[2,3-d]thiazole-5-carboxylate as a light yellow solid. MS: (ESI, m/z): 229 [M+H]⁺.

Step 3. 6-Amino-2-methylthieno[2,3-d]thiazole-5-carboxylic Acid

To a solution of methyl 6-amino-2-methylthieno[2,3-d]thiazole-5-carboxylate (174 mg, 0.76 mmol) in ACN (11 mL) was added a solution of LiOH (100 mg, 4.18 mmol) in water (5 mL). The resulting solution was stirred overnight at 30° C., then was concentrated under vacuum. The residue was diluted with 1 mL of water. The pH value of the residue was adjusted to 7 with 1N HCl solution. The solids were collected by filtration to give 6-amino-2-methylthieno[2,3-d]thiazole-5-carboxylic acid as an off-white solid. MS: (ESI, m/z): 214 [M+H]⁺.

To a solution of methyl 1H-pyrrolo[2,3-b]pyridine-5-carboxylate (3 g, 17.03 mmol) in DMF (80 mL) was added sodium hydride (2.04 g, 51.09 mmol, 60% dispersion in oil) in portions at 0° C. The reaction mixture was stirred for 1 h at 0° C. Then iodoethane (5.32 g, 34.06 mmol) was added at 0° C. The resulting solution was stirred for 10 h at room temperature. The reaction was quenched with 10 mL of water. After stirred for 30 min, the pH value of the solution was adjusted to 7-8 with 3N HCl. The resulting mixture was extracted with EtOAc (6×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give of 1-ethyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid as a yellow solid (crude, 90% purity). MS: (ESI, m/z): 191 [M+H]⁺.

Step 1. 3-Chloro-7-ethyl-7H-pyrrolo[2,3-c]pyridazine

To a solution of 3-chloro-7H-pyrrolo[2,3-c]pyridazine (700 mg, 4.56 mmol) in DMF (17 mL) was added NaH (365 mg, 9.12 mmol, 60% dispersion in oil) in portions at 0° C. The reaction mixture was stirred for 30 min at 0° C. Then iodoethane (856 mg, 5.49 mmol) was added at 0° C. and the reaction mixture was stirred for 2 h at room temperature. The reaction was quenched by the addition of 40 mL of water. The resulting mixture was extracted with EtOAc (3×20 mL).

The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by prep-TLC (eluting with 1:1 EtOAc/pet. ether) afforded 3-chloro-7-ethyl-7H-pyrrolo[2,3-c]pyridazine as yellow oil. MS: (ESI, m/z): 182, 183 [M+H]⁺.

Step 2. Methyl 7-ethyl-7H-pyrrolo[2,3-c]pyridazine-3-carboxylate

In a 30-mL pressure tank reactor, a solution of 3-chloro-7-ethyl-7H-pyrrolo[2,3-c]pyridazine (300 mg, 1.65 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (121 mg, 0.15 mmol), and Et₃N (0.69 mL, 4.96 mmol) in MeOH (15 mL) was stirred for 48 h at 120° C. under 50 atm of CO (g). After cooling to room temperature, the resulting mixture was concentrated under vacuum. The residue was diluted with 20 mL of water. The resulting mixture was extracted with EtOAc (3×20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by prep-TLC (eluting with 1:1 EtOAc/pet. ether) afforded methyl 7-ethyl-7H-pyrrolo[2,3-c]pyridazine-3-carboxylate as a yellow solid. MS: (ESI, m/z): 206 [M+H]⁺.

Step 3. 7-Ethyl-7H-pyrrolo[2,3-c]pyridazine-3-carboxylic Acid

A mixture of methyl 7-ethyl-7H-pyrrolo[2,3-c]pyridazine-3-carboxylate (238 mg, 1.04 mmol), and sodium hydroxide (206 mg, 5.20 mmol) in THF (10 mL) and water (10 mL was stirred for 18 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was diluted with 10 mL of water. The pH value of the mixture was adjusted to 5 with 2N HCl. The resulting mixture was extracted with EtOAc (3×30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give 7-ethyl-7H-pyrrolo[2,3-c]pyridazine-3-carboxylic acid as a light yellow solid (crude). MS: (ESI, m/z): 192 [M+H]⁺.

Step 1. Ethyl 3-amino-6-methylfuro[2,3-b]pyridine-2-carboxylate

A solution of 2-chloro-6-methylnicotinonitrile (5 g, 32.77 mmol), ethyl 2-hydroxyacetate (3.36 g, 32.28 mmol), and Cs₂CO₃ (32.2 g, 98.83 mmol) in NMP (80 mL) was stirred overnight at 75° C. After cooling to room temperature, the mixture was poured into 100 mL of water. The resulting mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:3 ethyl acetate/pet. ether) afforded ethyl 3-amino-6-methylfuro[2,3-b]pyridine-2-carboxylate as a pink solid. MS: (ESI, m/z): 221 [M+H]⁺.

Step 2. 3-Amino-6-methylfuro[2,3-b]pyridine-2-carboxylic Acid

To a solution of ethyl 3-amino-6-methylfuro[2,3-b]pyridine-2-carboxylate (110 mg, 0.53 mmol) in methanol (1 mL) and THF (1 mL) was added a solution of LiOH (24 mg, 1.00 mmol) in water (0.5 mL) dropwise with stirring. The resulting solution was stirred overnight at room temperature. The pH value of the solution was adjusted to 8 with 1N HCl. The resulting mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by reverse phase chromatography (Column: C₁₈ silica gel; Mobile phase A: water (0.1% formic acid), B: ACN; Flow rate: 50 mL/min; Gradient: 0% B to 100% B in 30 min) afforded 3-amino-6-methylfuro[2,3-b]pyridine-2-carboxylic acid as a light yellow solid. MS: (ESI, m/z): 193 [M+H]⁺.

Step 1. Methyl 5,6,7,8-tetrahydro-1,8-naphthyridine-3-carboxylate

In a 30-mL pressure tank reactor, a mixture of tert-butyl 6-bromo-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (300 mg, 0.86 mmol), Pd(dppf)Cl₂—CH₂Cl₂ (90 mg, 0.11 mmol), and Et₃N (1 mL) in MeOH (5 mL) was stirred for 48 h at 120° C. under 5 atm of CO (g). After cooling to room temperature, the solvent was removed under vacuum. The residue was diluted with water (10 mL) and was extracted with EtOAc (3×10 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:5 EtOAc/pet. ether) to afford 0.15 g of methyl 5,6,7,8-tetrahydro-1,8-naphthyridine-3-carboxylate as a white solid. MS: (ESI, m/z): 193 [M+H]⁺.

Step 2. 1-(tert-Butyl) 6-methyl 3,4-dihydro-1,8-naphthyridine-1,6(2H)-dicarboxylate

A solution of methyl 5,6,7,8-tetrahydro-1,8-naphthyridine-3-carboxylate (110 mg, 0.52 mmol), DMAP (126 mg, 1.03 mmol), and (Boc)₂O (227 mg, 1.04 mmol) in DMF (5 mL) was stirred for 1 h at room temperature. The reaction was quenched by the addition of 5 mL of water. The resulting mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:8 EtOAc/pet. ether) to afford 1-(tert-butyl) 6-methyl 3,4-dihydro-1,8-naphthyridine-1,6(2H)-dicarboxylate as a white solid. MS: (ESI, m/z): 293 [M+H]⁺.

Step 3. 8-(tert-Butoxycarbonyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carboxylic Acid

A solution of 1-(tert-butyl) 6-methyl 3,4-dihydro-1,8-naphthyridine-1,6(2H)-dicarboxylate (280 mg, 0.86 mmol) and LiOH (81 mg, 3.38 mmol) in THF (5 mL) and water (5 mL) was stirred for 3 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase chromatography (Column: C₁₈ silica gel; Mobile phase A: water (0.05% formic acid), B: ACN; Gradient: 0% B to 60% B in 40 min) to afford 8-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carboxylic acid as a white solid. MS: (ESI, m/z): 279 [M+H]⁺.

Step 1. 6-Bromo-1,2,3,4-tetrahydro-1,8-naphthyridine

To a solution of 6-bromo-3,4-dihydro-1,8-naphthyridin-2(1H)-one (5.0 g, 21.80 mmol) and NaBH₄ (4.18 g, 110.49 mmol) in THF (140 mL) was added BF₃-Et₂O (20 mL, 157.83 mmol) dropwise at 0° C. The reaction mixture was stirred for 16 h at room temperature. 1N HCl solution (100 mL) was added and the reaction mixture was stirred for an additional 16 h at room temperature. The pH value of the mixture was then adjusted to 8 with aq. sat. NaHCO₃ solution. The resulting mixture was extracted with ethyl acetate (3×150 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give 6-bromo-1,2,3,4-tetrahydro-1,8-naphthyridine as a white solid. MS: (ESI, m/z): 213, 215 [M+H]⁺.

Step 2. Tert-Butyl 6-bromo-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate

To a mixture of sodium hydride (1.41 g, 58.76 mmol, 60% dispersion in oil) in THF (100 mL) was added a solution of 6-bromo-1,2,3,4-tetrahydro-1,8-naphthyridine (5.0 g, 22.53 mmol) in THF (100 mL) at 0° C. The reaction mixture was stirred for 30 min at 0° C. To the mixture was then added a solution of (Boc)₂O (10.15 g, 46.51 mmol) in THF (50 mL). The resulting mixture was heated at reflux for 16 h. After cooling to room temperature, the reaction was quenched by the addition of water (150 mL). The resulting mixture was extracted with ethyl acetate (3×150 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:3 EtOAc/pet. ether) afforded tert-butyl 6-bromo-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate as a light yellow solid. MS: (ESI, m/z): 313, 315 [M+H]⁺.

Step 3. Tert-Butyl 6-bromo-4-oxo-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate

To a solution of tert-butyl 6-bromo-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (2.0 g, 6.13 mmol) and NaH₂PO₄ (1.92 g, 16.00 mmol) in tert-butanol (20 mL) and water (15 mL) was added a solution of NaMnO₄—H₂O (6.13 g, 38.31 mmol) in water (5 mL) dropwise at 50° C. The reaction mixture was stirred for 3 h at 50° C. After cooling to room temperature, Na₂SO₃ was added and the mixture was stirred for 30 min at room temperature. The solids were filtered away and the filtrate was diluted with 50 mL of water. The resulting mixture was extracted with ethyl acetate (3×50 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:3 EtOAc/pet. ether) afforded tert-butyl 6-bromo-4-oxo-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate as a white solid. MS: (ESI, m/z): 327, 329 [M+H]⁺.

Step 4. Tert-Butyl 6-bromo-4-methylene-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate

A solution of methyltriphenylphosphonium bromide (3.29 g, 9.21 mmol) and t-BuOK (1M in THF) (9.2 mL, 9.02 mmol) in toluene (30 mL) was stirred for 1 h at 100° C. To the reaction mixture was added a solution of tert-butyl 6-bromo-4-oxo-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (1.5 g, 4.40 mmol) in toluene (5 mL). The resulting solution was for 1 h at 100° C. After cooling to room temperature, the reaction was quenched by the addition of water (50 mL). The resulting mixture was extracted with ethyl acetate (3×50 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography (eluting with gradient 1:100 to 1:3 EtOAc/pet. ether) afforded tert-butyl 6-bromo-4-methylene-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate as a white solid. MS: (ESI, m/z): 325, 327 [M+H]⁺.

Step 5. Tert-Butyl 6′-bromo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-[1,8]naphthyridine]-1′-carboxylate

To a solution of potassium hydroxide (4.8 g, 85.55 mmol) in water (7.2 mL) was added a solution of 2-nitrosopropanamide (3.76 g, 36.83 mmol) in Et₂O (30 mL) was added. The resulting solution was stirred for 1 h at 0° C. The organic phase was separated to obtain the solution of diazomethane in Et₂O. To a solution of tert-butyl 6-bromo-4-methylene-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (400 mg, 1.18 mmol) in THF (30 mL) was added the solution of diazomethane at 0° C., followed by the addition of a mixture of Pd(OAc)₂ (28 mg, 0.12 mmol) in THF (3 mL). The reaction mixture was stirred for an additional 3 h at room temperature. The solids were filtered away and the filtrate was concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:3 EtOAc/pet. ether) afforded tert-butyl 6′-bromo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-[1,8]naphthyridine]-1′-carboxylate as a light yellow solid. MS: (ESI, m/z): 339, 341 [M+H]⁺.

Step 6. 2′,3′-Dihydro-1′H-spiro[cyclopropane-1,4′-[1,8]naphthyridine]-6′-carboxylic Acid

Into a 30-mL pressure tank reactor fitted with a magnetic stir bar, was placed a mixture of tert-butyl 6′-bromo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-[1,8]naphthyridine]-1′-carboxylate (140 mg, 0.40 mmol), sodium acetate trihydrate (167 mg, 1.23 mmol), and Pd(dppf)Cl₂—CH₂Cl₂ (65 mg, 0.08 mmol) in DMF (6 mL) and water (2 mL). The reaction mixture was stirred for 16 h at 120° C. under an atmosphere of carbon monoxide at 50 atm. After cooling to room temperature, the reaction was quenched by the addition of 20 mL of water. The resulting solution was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by reverse phase chromatography (Column: C₁₈ silica gel; Mobile phase A: water, B: ACN; Gradient: 0% B to 10% B in 10 min) afforded 2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-[1,8]naphthyridine]-6′-carboxylic acid as an off-white solid. MS: (ESI, m/z): 205 [M+H]⁺.

Step 1. 2-(Allylamino)-5-bromonicotinaldehyde

Into two parallel 30 ml sealed tubes, each was placed 5-bromo-2-fluoronicotinaldehyde (1.83 g, 9.0 mmol), allylamine (1.03 g, 18.0 mmol) and ethanol (15 mL). The resulting solution was stirred for 3 h at 80° C. After cooling room temperature, the resulting solution was poured into 30 mL of hydrochloric acid (1N) and the resulting mixture was stirred for 10 min and then extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:10 EtOAc/pet. ether) afforded 2-(allylamino)-5-bromonicotinaldehyde as a light yellow solid. MS: (ESI, m/z): 241, 243 [M+H]⁺.

Step 2. N-Allyl-5-bromo-3-vinylpyridin-2-amine

A solution of methyltriphenylphosphonium bromide (6.22 g, 17.42 mmol) and potassium tert butoxide (1.96 g, 17.42 mmol) in THF (30 mL) was stirred for 1 h at room temperature. Then a solution of 2-(allylamino)-5-bromonicotinaldehyde (2.10 g, 87.1 mmol) in THF (5 mL) was added dropwise at room temperature and the reaction mixture was stirred overnight at room temperature. The reaction was quenched by the addition of 20 mL of water and was extracted with DCM (3×40). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:20 EtOAc/pet. ether) afforded N-allyl-5-bromo-3-vinylpyridin-2-amine as a light yellow liquid. MS: (ESI, m/z): 239, 241 [M+H]⁺.

Step 3. Tert-Butyl allyl(5-bromo-3-vinylpyridin-2-yl)carbamate

A solution of N-allyl-5-bromo-3-vinylpyridin-2-amine (590 mg, 2.47 mmol), di-tert-butyl dicarbonate (1.62 g, 7.40 mmol), triethylamine (749 mg, 7.40 mmol) and 4-dimethylaminopyridine (90 mg, 0.74 mmol) in THF (15 mL) was stirred overnight at 70° C. After cooling to room temperature, the reaction was quenched by the addition of 50 mL of water. The resulting mixture was extracted with ethyl acetate (3×40 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:30 EtOAc/pet. ether) afforded tert-butyl allyl(5-bromo-3-vinylpyridin-2-yl)carbamate as an off-white solid. MS: (ESI, m/z): 339, 341 [M+H]⁺.

Step 4. Tert-Butyl 6-bromo-1,8-naphthyridine-1(2H)-carboxylate

A solution of tert-butyl allyl(5-bromo-3-vinylpyridin-2-yl)carbamate (600 mg, 1.77 mmol) and dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](benzylidene)(tricyclohexylphosphine)ruthenium(II) (Grubbs Catalyst™ 2^(nd) Gen) (75 mg, 0.09 mmol) in DCM (10 mL) was stirred overnight at 50° C. After cooling to room temperature, the resulting mixture was concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:20 EtOAc/pet. ether) afforded tert-butyl 6-bromo-1,8-naphthyridine-1(2H)-carboxylate as an off-white solid. MS: (ESI, m/z): 311, 313 [M+H]⁺.

Step 5. Tert-Butyl 6-bromo-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyridine-3-carboxylate

To a solution of potassium hydroxide (5.68 g, 101.24 mmol) in water (8 mL) was added a solution of 1-methyl-1-nitrosourea (2.98 g, 28.92 mmol) in Et₂O (40 mL) dropwise at 0° C. The reaction mixture was stirred for 1 h at 0° C. Then the organic phase was separated to obtain the solution of diazomethane in Et₂O. To a solution of tert-butyl 6-bromo-1,8-naphthyridine-1(2H)-carboxylate (450 mg, 1.45 mmol) in THF (15 mL) was added the solution of diazomethane in Et₂O (40 mL), followed by the addition of a solution of Pd(OAc)₂ (32 mg, 0.14 mmol) in THF (7 mL). The resulting solution was stirred overnight at room temperature. The solids were filtered away and the filtrate was concentrated under vacuum. Purification by silica gel chromatography (eluting with gradient 1:50 to 1:20 EtOAc/pet. ether) afforded tert-butyl 6-bromo-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyridine-3-carboxylate as an off-white solid. MS: (ESI, m/z): 325, 327 [M+H]⁺.

Step 6. 3-(tert-Butoxycarbonyl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine-6-carboxylic Acid

Into a 30-mL pressure tank reactor, was placed tert-butyl 6-bromo-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyridine-3-carboxylate (200 mg, 0.62 mmol), Pd(dppf)Cl₂ (90 mg, 0.12 mmol), NaOAc (151 mg, 1.85 mmol), DMF (4.5 mL) and water (1.5 mL). The reaction mixture was stirred for 18 h at 120° C. under 50 atm of CO (g). After cooling to room temperature, the reaction mixture was diluted with 10 mL of water. The resulting mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by reverse phase chromatography (Column: C₁₈ silica gel; Mobile phase A: water (0.1% formic acid), B: ACN; Flow rate: 50 mL/min; Gradient: 0% B to 100% B in 30 min) afforded 3-(tert-butoxycarbonyl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine-6-carboxylic acid as a light yellow solid. MS: (ESI, m/z): 291 [M+H]⁺.

Step 1. Methyl 6-(benzylamino)nicotinate

A mixture of methyl 6-fluoropyridine-3-carboxylate (1 g, 6.12 mmol), phenylmethanamine (1.38 g, 12.88 mmol), and potassium carbonate (2.67 g, 19.32 mmol) in DMF (10 mL) was stirred for 2 h at 80° C. After cooling to room temperature, the reaction was quenched by the addition of 20 mL of water. The resulting mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography (eluting with 3:10 EtOAc:pet. ether) afforded methyl 6-(benzylamino)nicotinate as a white solid. MS: (ESI, m/z): 243 [M+H]⁺.

Step 2. 6-(Benzylamino)nicotinic Acid

A mixture of methyl 6-(benzylamino)nicotinate (500 mg, 1.86 mmol), methanol (20 mL), water (2 mL), and NaOH (165 mg, 4.13 mmol) was stirred for 3 h at 80° C. After cooling to room temperature, the resulting mixture was concentrated under vacuum. The residue was dissolved in 10 mL of water. The pH value of the solution was adjusted to 6 with hydrochloric acid (6 N). The solids were collected by filtration to afford 6-(benzylamino)nicotinic acid as a white solid. MS: (ESI, m/z): 229 [M+H]⁺.

Step 1: tert-Butyl 7-benzyl-9,9-difluoro-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate

A solution of tert-butyl 7-benzyl-9-oxo-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (5 g, 14.94 mmol) and DAST (12.2 g, 75.69 mmol) in CH₂Cl₂ (80 mL) was stirred for 16 h at room temperature. The reaction was then quenched by the addition of 50 mL of saturated aqueous NaHCO₃ solution. The resulting mixture was extracted with CH₂Cl₂ (100 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with 5:1 pet. ether/EtOAc) afforded 700 mg of tert-butyl 7-benzyl-9,9-difluoro-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate as a yellow solid. MS: (ESI, m/z): 353 [M+H]⁺.

Step 2: Tert-Butyl 9,9-difluoro-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate

A mixture of tert-butyl 7-benzyl-9,9-difluoro-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (460 mg, 1.24 mmol) and Pd/C (50 mg, 10%) in EtOAc (20 mL) was stirred at 50° C. for 2 h under an atmosphere of hydrogen. After cooling to room temperature, the solids were filtered away and the filtrate was concentrated under vacuum. The residue was purified by pre-HPLC (Column: XBridge Prep C18 OBD, 19×250 mm; Mobile phase A: water (10 mM NH₄HCO₃), B: ACN; Gradient: 20% B to 45% B in 7 min) to afford tert-butyl 9,9-difluoro-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate as a light yellow solid. MS: (ESI, m/z): 263 [M+H]⁺.

Step 1. Methyl 2-(3-(nitromethyl)oxetan-3-ylamino)acetate

To a solution of oxetan-3-one (5 g, 69.38 mmol), nitromethane (5.93 g, 97.15 mmol), and Et₃N (2.1 g, 13.28 mmol) in DCM (70 mL) was added a solution of MsCl (10 g, 87.30 mmol) in DCM (70 mL) at −80° C. Stirring continued at −80° C. for an additional 90 min. Separately, a solution of glycine ethyl ester hydrochloride (19.4 g, 139 mmol) and Et₃N (21 g, 139 mmol) in DCM (300 mL) was allowed to react, with stirring, for 10 min at room temperature. The resulting solution was added into the first reaction mixture at −80° C. in portions. After addition, the reaction mixture was stirred for 16 h at room temperature. The reaction was quenched by the addition of 100 mL of water and was extracted with 2×300 mL of DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by prep-HPLC (Column:)(Bridge Prep C18 OBD, 19×150 mm, 5 μm; Mobile phase A: water (10 mM NH₄HCO₃), B: ACN; Gradient: 10% B to 50% B in 30 min) afforded methyl 2-(3-(nitromethyl)oxetan-3-ylamino)acetate as a yellow oil. MS: (ESI, m/z): 205 [M+H]⁺.

Step 2. 2-Oxa-5,8-diazaspiro[3.5]nonan-7-one

A suspension of methyl 2-(3-(nitromethyl)oxetan-3-ylamino)acetate (8.5 g, 41.63 mmol) and Raney Ni (2 g) in MeOH (50 mL) was stirred for 16 h at room temperature under an atmosphere of hydrogen. The solids were filtered away and the filtrate was concentrated under vacuum. Purification by prep-HPLC (Column:)(Bridge Prep C18 OBD, 19×150 mm, 5 μm; Mobile phase A: water (10 mM NH₄HCO₃), B: ACN; Gradient: 10% B to 80% B in 30 min) afforded 2-oxa-5,8-diazaspiro[3.5]nonan-7-one as a red solid. MS: (ESI, m/z): 143 [M+H]⁺.

Step 3. 5-Benzyl-2-oxa-5,8-diazaspiro[3.5]nonan-7-one

A mixture of 2-oxa-5,8-diazaspiro[3.5]nonan-7-one (4 g, 28.14 mmol), (bromomethyl)benzene (12 g, 70.16 mmol), Na₂CO₃ (20.9 g, 197.18 mmol), and NaI (10.5 g, 70.05 mmol) in acetonitrile (200 mL) was stirred for 3 h at 80° C. After cooling to room temperature, the solvent was removed under vacuum. The residue was diluted with water (200 mL). The resulting mixture was extracted with DCM (2×300 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:10 MeOH/CH₂C₁₂) afforded 5-benzyl-2-oxa-5,8-diazaspiro[3.5]nonan-7-one as a yellow solid. MS: (ESI, m/z): 233 [M+H]⁺.

Step 4. 5-Benzyl-2-oxa-5,8-diazaspiro[3.5]nonane-7-thione

A solution of 5-benzyl-2-oxa-5,8-diazaspiro[3.5]nonan-7-one (2.9 g, 11.86 mmol) and 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane (Lawesson reagent) (2.44 g, 6.03 mmol) in THF (150 mL) was stirred for 16 h at room temperature and then stirred for an additional 3 h at 65° C. The reaction mixture was then poured into water (100 mL) and was extracted with DCM (2×150 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:3 EtOAc/pet. ether) afforded 5-benzyl-2-oxa-5,8-diazaspiro[3.5]nonane-7-thione as a white solid. MS: (ESI, m/z): 249 [M+H]⁺.

Step 5. 5-Benzyl-2-oxa-5,8-diazaspiro[3.5]nonane

A solution of 5-benzyl-2-oxa-5,8-diazaspiro[3.5]nonane-7-thione (300 mg, 1.15 mmol) and sodium borohydride (412 mg, 11.19 mmol) in THF (15 mL) and MeOH (30 mL) was stirred for 2 h at room temperature. The reaction was quenched with water (15 mL) and was stirred for an additional 14 h at room temperature. The resulting mixture was extracted with DCM (2×50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by prep-HPLC (Column: XBridge Prep C18 OBD, 19×150 mm, 5 μm; Mobile phase A: water (10 mM NH₄HCO₃), B: ACN; Gradient: 10% B to 75% B in 30 min) afforded 5-benzyl-2-oxa-5,8-diazaspiro[3.5]nonane as a white solid. MS: (ESI, m/z): 219 [M+H]⁺.

Step 1. Tert-Butyl 5-benzyl-2-oxa-5,8-diazaspiro[3.5]nonane-8-carboxylate

A solution of 5-benzyl-2-oxa-5,8-diazaspiro[3.5]nonane, Intermediate 31, (200 mg, 0.82 mmol), (Boc)₂O (200 mg, 0.92 mmol), Et₃N (185 mg, 1.83 mmol), and 4-dimethylaminopyridine (11 mg, 0.09 mmol) in DCM (4 mL) was stirred for 2.5 h at room temperature. The reaction was quenched by the addition of water (20 mL) and was extracted with EtOAc (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:4 EtOAc/pet. ether) afforded of tert-butyl 5-benzyl-2-oxa-5,8-diazaspiro[3.5]nonane-8-carboxylate as a yellow oil. MS: (ESI, m/z): 319 [M+H]⁺.

Step 2. Tert-Butyl 2-oxa-5,8-diazaspiro[3.5]nonane-8-carboxylate

A mixture of tert-butyl 5-benzyl-2-oxa-5,8-diazaspiro[3.5]nonane-8-carboxylate (190 mg, 0.60 mmol) and Pd/C (20 mg, 10%) in EtOAc (10 mL) was stirred for 1 h at room temperature. The solids were filtered away and the filtrate was concentrated under vacuum to afford tert-butyl 2-oxa-5,8-diazaspiro[3.5]nonane-8-carboxylate as a yellow oil. MS: (ESI, m/z): 229 [M+H]⁺.

Step 1. Benzyl 3-azido-4-hydroxypyrrolidine-1-carboxylate

A solution of benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (5 g, 22.81 mmol), NaN₃ (3 g, 46.15 mmol), NH₄C₁ (1.23 g, 22.99 mmol) in MeOH (60 mL) and water (10 mL) was stirred for 16 h at 65° C. After cooling to room temperature, the pH value was adjusted to 7-8 with aq. 0.5N NaOH. The resulting mixture was extracted with DCM (2×150 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give benzyl 3-azido-4-hydroxypyrrolidine-1-carboxylate as light-yellow solid. MS: (ESI, m/z): 263 [M+H]⁺.

Step 2. Benzyl 3-azido-4-methoxypyrrolidine-1-carboxylate

To a solution of benzyl 3-azido-4-hydroxypyrrolidine-1-carboxylate (4 g, 15.25 mmol) in DMF (40 mL) was added NaH (1.2 g, 60% dispersion in oil) at <10° C. The resulting solution was stirred for 1 h at room temperature. Iodomethane (2.8 mL, 44.98 mmol) was added and stirring was continued for another 1 h. The reaction was quenched by the addition of water (50 mL). The resulting mixture was extracted with Et₂O (2×50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:1 EtOAc/pet. ether) afforded benzyl 3-azido-4-methoxypyrrolidine-1-carboxylate as a colorless oil. MS: (ESI, m/z): 277 [M+H]⁺.

Step 3. Benzyl 3-amino-4-methoxypyrrolidine-1-carboxylate

A solution of benzyl 3-azido-4-methoxypyrrolidine-1-carboxylate (2 g, 7.24 mmol) and PPh₃ (2.1 g, 8.01 mmol) in THF (50 mL) and water (5 mL) was stirred for 1 h at room temperature, then for an additional 5 h at 50° C. After cooling to room temperature, the reaction was concentrated under vacuum. Purification by prep-HPLC (Column: XBridge Prep C18 OBD, 19×50 mm, 5 μm; Mobile phase A: water (10 mM NH₄HCO₃), B: ACN; Gradient: 10% B to 80% B in 30 min) afforded benzyl 3-amino-4-methoxypyrrolidine-1-carboxylate as a colorless oil. MS: (ESI, m/z): 251 [M+H]⁺.

Step 4. Benzyl 3-((tert-butoxycarbonyl)amino)-4-methoxypyrrolidine-1-carboxylate

A solution of benzyl 3-amino-4-methoxypyrrolidine-1-carboxylate (600 mg, 2.40 mmol), Et₃N (457 mg, 4.52 mmol), and (Boc)₂O (786 mg, 3.60 mmol) in THF (12 mL) and water (12 mL) was stirred for 30 min at room temperature. The resulting mixture was extracted with DCM (2×30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:1 EtOAc/pet. ether) to give benzyl 3-((tert-butoxycarbonyl)amino)-4-methoxypyrrolidine-1-carboxylate as a white solid. MS: (ESI, m/z): 351 [M+H]⁺.

Step 5. Tert-Butyl N-(4-methoxypyrrolidin-3-yl)carbamate

A mixture of benzyl 3-((tert-butoxycarbonyl)amino)-4-methoxypyrrolidine-1-carboxylate (200 mg, 0.57 mmol) and Pd/C (200 mg, 10%) in EtOAc (10 mL) was stirred for 3 h at room temperature under an atmosphere of hydrogen. The solids were filtered out and washed with EtOAc (3×10 mL). The filtrate was concentrated under vacuum to give tert-butyl N-(4-methoxypyrrolidin-3-yl)carbamate as a white solid. MS: (ESI, m/z): 217 [M+H]⁺.

Step 1. Benzyl (3S,4S)-3-azido-4-hydroxypyrrolidine-1-carboxylate

To a mixture of benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (10 g, 44.70 mmol) and (1R,2R)-(−)-[1,2-cyclohexanediamino-N N′-bis(3,5-di-t-butylsalicylidene)]chromium (III) chloride (Jacobsen's Chromium catalyst) (682 mg, 1.08 mmol) was added azidotrimethylsilane (6.52 g, 56.59 mmol) at 30° C. The reaction mixture was stirred for 16 h at 30° C. Methanol (30 mL) and trifluoroacetic acid (0.5 mL) were added. The resulting solution was stirred at 30° C. for 3 h, then concentrated under vacuum. The residue was diluted with 100 mL of water and was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:2 EtOAc/pet.ether) afforded benzyl (3S,4S)-3-azido-4-hydroxypyrrolidine-1-carboxylate as a light yellow oil. MS: (ESI, m/z): 263 [M+H]⁺.

Step 2. Benzyl (3S,4S)-3-azido-4-methoxypyrrolidine-1-carboxylate

The title compound was prepared according to the procedures of Intermediate 35, Step 2, starting from benzyl (3S,4S)-3-azido-4-hydroxypyrrolidine-1-carboxylate. MS: (ESI, m/z): 277 [M+H]⁺.

Step 3. Benzyl (3S,4S)-3-amino-4-methoxypyrrolidine-1-carboxylate

The title compound was prepared according to the procedures of Intermediate 35, Step 3, starting from benzyl (3S,4S)-3-azido-4-methoxypyrrolidine-1-carboxylate. MS: (ESI, m/z): 251 [M+H]⁺.

Step 4. Benzyl (3S,4S)-3-((tert-butoxycarbonyl)amino)-4-methoxypyrrolidine-1-carboxylate

The title compound was prepared according to the procedures of Intermediate 35, Step 4, starting from benzyl (3S,4S)-3-amino-4-methoxypyrrolidine-1-carboxylate. MS: (ESI, m/z): 351 [M+H]⁺.

Step 5. Tert-butyl ((3S,4S)-4-methoxypyrrolidin-3-yl)carbamate

The title compound was prepared according to the procedures of Intermediate 35, Step 5, starting from benzyl (3S,4S)-3-((tert-butoxycarbonyl)amino)-4-methoxypyrrolidine-1-carboxylate. MS: (ESI, m/z): 217 [M+H]⁺.

Step 1. 1-Benzyl 3-methyl 3-(trifluoromethyl)piperidine-1,3-dicarboxylate

To a solution of 1-benzyl 3-methyl piperidine-1,3-dicarboxylate (2.0 g, 7.14 mmol) in THF (60 mL) was added LDA (2.0 M in THF) (10.8 mL, 21.66 mmol) dropwise at −78° C. After the solution was stirred for 30 min at −78° C., S-(trifluoromethyl)dibenzothiophenium trifluoromethanesulfonate (4.35 g, 10.81 mmol) was added. After addition, the resulting solution was allowed to react, with stirring, for an additional 2 h at −40° C. The reaction was then quenched by the addition of 30 mL of a saturated aqueous solution of NH₄C₁. The resulting mixture was extracted with EtOAc (3×70 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:4 EtOAc/pet. ether) afforded 1-benzyl 3-methyl 3-(trifluoromethyl)piperidine-1,3-dicarboxylate as a yellow oil. MS: (ESI, m/z): 346 [M+H]⁺.

Step 2. 1-((Benzyloxy)carbonyl)-3-(trifluoromethyl)piperidine-3-carboxylic Acid

A solution of 1-benzyl 3-methyl 3-(trifluoromethyl)piperidine-1,3-dicarboxylate (310 mg, 0.83 mmol) in MeOH (10 mL) and aq. 1N NaOH (2.7 mL, 2.70 mmol) was stirred for 2 h at 50° C. and then concentrated under vacuum. The residue was diluted with 5 mL of water. The pH value of the solution was adjusted to 3-4 with 6N HCl. The solids were collected by filtration to give of 1-((benzyloxy)carbonyl)-3-(trifluoromethyl)piperidine-3-carboxylic acid as a yellow solid. MS: (ESI, m/z): 332 [M+H]⁺.

Step 3. Benzyl 3-((tert-butoxycarbonyl)amino)-3-(trifluoromethyl)piperidine-1-carboxylate

A solution of 1-((benzyloxy)carbonyl)-3-(trifluoromethyl)piperidine-3-carboxylic acid (250 mg, 0.76 mmol), Et₃N (229 mg, 2.26 mmol), and DPPA (415 mg, 1.51 mmol) in toluene (8 mL) was stirred for 2 h at 90° C. tert-Butanol (279 mg, 3.76 mmol) was added and the reaction mixture was stirred for an additional 16 h at 90° C. After cooling to room temperature, the reaction was quenched by the addition of water (20 mL) and was extracted with EtOAc (20 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:10 to 1:3 EtOAc/pet. ether) afforded benzyl 3-((tert-butoxycarbonyl)amino)-3-(trifluoromethyl)piperidine-1-carboxylate as a yellow solid. MS: (ESI, m/z): 403 [M+H]⁺.

Step 4. Tert-Butyl (3-(trifluoromethyl)piperidin-3-yl)carbamate

A mixture of benzyl 3-((tert-butoxycarbonyl)amino)-3-(trifluoromethyl)piperidine-1-carboxylate (90 mg, 0.21 mmol) and Pd/C (10 mg, 10%) in EtOAc (5 mL) was stirred for 1 h at room temperature under an atmosphere of hydrogen. The solids were filtered away and the filtrate was concentrated under vacuum to give tert-butyl (3-(trifluoromethyl)piperidin-3-yl)carbamate as yellow oil. MS: (ESI, m/z): 269 [M+H]⁺.

Step 1. Benzyl 3-azido-4-hydroxypyrrolidine-1-carboxylate

A solution of benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (5 g, 22.81 mmol), NaN₃ (3 g, 46.15 mmol), NH₄C₁ (1.23 g, 22.99 mmol) in MeOH (60 mL) and water (10 mL) was stirred for 16 h at 65° C. After cooling to room temperature, the pH value was adjusted to 7-8 with aq. 0.5N NaOH. The resulting mixture was extracted with DCM (2×150 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give benzyl 3-azido-4-hydroxypyrrolidine-1-carboxylate as light-yellow solid. MS: (ESI, m/z): 263 [M+H]⁺.

Step 2. Benzyl 3-((tert-butoxycarbonyl)amino)-4-hydroxypyrrolidine-1-carboxylate

A solution of benzyl 3-azido-4-hydroxypyrrolidine-1-carboxylate (6 g, 22.88 mmol), aq. 1 N NaOH (46 mL, 46 mmol), PMe₃ (1M in THF) (70 mL, 70 mmol), and (Boc)₂O (15.0 g, 68.73 mmol) in THF (228 mL) was stirred for 3 h at room temperature. The reaction mixture was diluted with 50 mL of water and was extracted with CH₂Cl₂ (3×200 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. Purification by reverse phase chromatography (Column: C₁₈ silica gel; Mobile phase A: water (10 mM NH₄HCO₃), B: ACN; Flow rate: 50 mL/min; Gradient: 0% B to 70% B in 40 min) afforded benzyl 3-((tert-butoxycarbonyl)amino)-4-hydroxypyrrolidine-1-carboxylate as a white solid. MS: (ESI, m/z): 337 [M+H]⁺.

Step 3. Benzyl 3-((tert-butoxycarbonyl)amino)-4-(trifluoromethoxy)pyrrolidine-1-carboxylate

A solution of benzyl 3-((tert-butoxycarbonyl)amino)-4-hydroxypyrrolidine-1-carboxylate (1 g, 2.97 mmol), Selectfluor® (5.26 g, 14.85 mmol), AgOTf (7.6 g, 29.7 mmol), KF (1.72 g, 29.61 mmol), 2-fluoropyridine (2.88 g, 29.66 mmol) and TMS-CF₃ (4.22 g, 29.68 mmol) in EtOAc (14 mL) was stirred overnight at room temperature. The solids were filtered out and washed with CH₂Cl₂ (3×50 mL). The combined filtrate was concentrated under vacuum and purified by reverse phase chromatography (Column: C₁₈ silica gel; Mobile phase A: water (10 mM NH₄HCO₃), B: ACN; Flow rate: 50 mL/min; Gradient: 0% B to 80% B in 40 min) to give benzyl 3-((tert-butoxycarbonyl)amino)-4-(trifluoromethoxy)pyrrolidine-1-carboxylate as yellow oil. MS: (ESI, m/z): 405 [M+H]⁺.

Step 4. Tert-Butyl (4-(trifluoromethoxy)pyrrolidin-3-yl)carbamate

A mixture of benzyl 3-((tert-butoxycarbonyl)amino)-4-(trifluoromethoxy)pyrrolidine-1-carboxylate (190 mg, 0.47 mmol) and Pd/C (20 mg, 10%) in EtOAc (10 mL) was stirred for 2 h at room temperature under an atmosphere of hydrogen. The solids were filtered away and the filtrate was concentrated under vacuum to give tert-butyl (4-(trifluoromethoxy)pyrrolidin-3-yl)carbamate as a yellow oil. MS: (ESI, m/z): 271 [M+H]⁺.

Step 1. 1-Benzyl-4-(tert-butyldimethylsilyloxy)piperidine

A solution of 1-benzylpiperidin-4-ol (1 g, 5.23 mmol), imidazole (712 mg, 10.46 mmol), and tert-butyldimethylsilyl chloride (867 mg, 5.75 mmol) in DCM (20 mL) was stirred for 3 h at room temperature and then diluted with 20 mL of water. The resulting mixture was extracted with DCM (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:3 EtOAc/pet. ether) afforded 1-benzyl-4-(tert-butyldimethylsilyloxy)piperidine as colorless oil. MS: (ESI, m/z): 306 [M+H]⁺.

Step 2. 4-(tert-Butyldimethylsilyloxy)piperidine

A mixture of 1-benzyl-4-(tert-butyldimethylsilyloxy)piperidine (500 mg, 1.64 mmol) and Pd/C (50 mg, 10%) in EtOAc (20 mL) was stirred for 2 h at room temperature under an atmosphere of hydrogen. The solids were filtered out and the filtrate was concentrated under vacuum to give 4-(tert-butyldimethylsilyloxy)piperidine as colorless oil. MS: (ESI, m/z): 216 [M+H]⁺.

A solution of 3-methylpiperidin-3-ol (500 mg, 3.91 mmol), tert-butyldimethylsilyl chloride (497 mg, 3.30 mmol), and Et₃N (837 mg, 8.27 mmol) in DCM (20 mL) was stirred for 24 h at room temperature. The reaction was quenched by the addition of 50 mL of water. The resulting mixture was extracted with DCM (3×40 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with gradient 1:20 to 1:5 EtOAc/pet. ether) afforded 3-((tert-butyldimethylsilyl)oxy)-3-methylpiperidine as colorless oil. MS: (ESI, m/z): 230 [M+H]⁺.

Step 1. Tert-Butyl 3-(2-ethoxy-2-oxoethylidene)azetidine-1-carboxylate

To a solution of ethyl 2-(diethoxyphosphoryl)acetate (26.2 g, 116.86 mmol) in THF (60 mL) was added NaH (4.68 g, 117.01 mmol, 60% dispersion in oil) in portions at 0° C. The resulting solution was stirred for 30 min at room temperature. To the reaction mixture was added tert-butyl 3-oxoazetidine-1-carboxylate (10 g, 58.41 mmol) with stirring at 0° C. The resulting solution was stirred for an additional 30 min at room temperature. The reaction was then quenched by the addition of 30 mL of a water/ice mixture. The resulting solution was extracted with DCM (3×40 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:5 EtOAc/pet. ether) afforded tert-butyl 3-(2-ethoxy-2-oxoethylidene)azetidine-1-carboxylate as yellow oil. MS: (ESI, m/z): 242 [M+H]⁺.

Step 2: 2-(tert-Butyl) 8-ethyl 7-oxo-5-oxa-2-azaspiro[3.4]octane-2,8-dicarboxylate

To a solution of NaH (1.2 g, 30.00 mmol, 60% dispersion in oil) in Et₂O (20 mL) was added methyl 2-hydroxyacetate (2.69 g, 29.86 mmol) at 0° C. The resulting solution was stirred for 30 min at room temperature and then concentrated under vacuum. The residue was diluted with 20 mL of DMSO and tert-butyl 3-(2-ethoxy-2-oxoethylidene)azetidine-1-carboxylate (6 g, 24.87 mmol) was added. The resulting solution was stirred overnight at room temperature. The pH value of the solution was adjusted to 4-5 with hydrochloric acid (1N). The resulting mixture was extracted with Et₂O (4×20 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. Purification by silica gel chromatography (eluting with gradient 1:10 to 1:5 EtOAc/pet. ether) afforded 2-(tert-butyl) 8-ethyl 7-oxo-5-oxa-2-azaspiro[3.4]octane-2,8-dicarboxylate as a light yellow solid. MS: (ESI, m/z): 300 [M+H]⁺.

Step 3. Tert-Butyl 7-oxo-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

A solution of 2-(tert-butyl) 8-ethyl 7-oxo-5-oxa-2-azaspiro[3.4]octane-2,8-dicarboxylate (4 g, 13.4 mmol) and NaCl (1.33 g, 22.76 mmol) in DMSO/water (10:1, 20 mL) was stirred for 2 h at 120° C. After cooling to room temperature, the reaction was quenched with 20 mL of water. The resulting mixture was extracted with Et₂O (4×20 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:3 EtOAc/pet. ether) afforded tert-butyl 7-oxo-5-oxa-2-azaspiro[3.4]octane-2-carboxylate as a white solid. MS: (ESI, m/z): 228 [M+H]⁺.

Step 4. Tert-Butyl 7-hydroxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate

To a solution of tert-butyl 7-oxo-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (1.1 g, 4.84 mmol) in THF (8 mL) was added NaH (276 mg, 7.49 mmol) in portions at 0° C. The resulting mixture was stirred for 30 min at room temperature. The reaction was quenched with 50 mL of a water/ice mixture. The resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. Purification by reverse phase chromatography (Column: C₁₈ silica gel; Mobile phase A: water (0.5% TFA), B: ACN; Gradient: 0% to 50% B over 35 min) afforded tert-butyl 7-hydroxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate as yellow oil. MS: (ESI, m/z): 230 [M+H]⁺.

Step 1. (4,6-Dichloropyridin-3-yl)methanol

Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4,6-dichloronicotinaldehyde (8 g, 43.18 mmol) and ethanol (200 mL). NaBH₄ (5.2 g, 141.21 mmol) was added in portions at 0° C. Then the resulting solution was stirred for 2 h at 25° C. The reaction was then quenched by the addition of water (200 mL). The resulting mixture was extracted with DCM (3×300 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:10 ethyl acetate/pet. ether) to give of ((4,6-dichloropyridin-3-yl)methanol as a colorless oil. MS: (ESI, m/z): 178,180 [M+H]⁺.

Step 2. 5-(Bromomethyl)-2,4-dichloropyridine

Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed (4,6-dichloropyridin-3-yl)methanol (5 g, 26.68 mmol), DCM (100 mL) and PBr₃ (7.7 g, 28.45 mmol). The resulting solution was stirred for 30 min at 40° C. in an oil bath. After cooling to 25° C., the reaction was then quenched by the addition of water (120 mL). The resulting mixture was extracted with DCM (2×150 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:30 ethyl acetate/pet. ether) to give 5-(bromomethyl)-2,4-dichloropyridine as a colorless oil. MS: (ESI, m/z): 240, 242, 244 [M+H]⁺.

Step 3. (2R,5S)-2-((4,6-Dichloropyridin-3-yl)methyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine

Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed (2S)-3,6-dimethoxy-2-(propan-2-yl)-2,5-dihydropyrazine (3 g, 15.47 mmol) and THF (200 mL). A solution of n-BuLi in n-hexane (2.5 M) (9.8 mL, 24.5 mmol) was added at −80° C. in a liquid nitrogen bath. The resulting solution was stirred for 30 min at −80° C. in a liquid nitrogen bath. Then a solution of 5-(bromomethyl)-2,4-dichloropyridine (4.7 g, 18.53 mmol) in THF (10 mL) was added. The resulting solution was allowed to react, with stirring, for an additional 1 h while the temperature was maintained at −80° C. in a liquid nitrogen bath. The reaction was then quenched by the addition of 120 mL of ammonium chloride (sat. aq.). The resulting mixture was extracted with DCM (2×150 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:10 ethyl acetate/pet. ether) to afford (2R,5S)-2-[(4,6-dichloropyridin-3-yl)methyl]-3,6-dimethoxy-5-(propan-2-yl)-2,5-dihydropyrazine as a white solid. MS: (ESI, m/z): 344, 346 [M+H]⁺.

Step 4. Methyl (2R)-2-amino-3-(4,6-dichloropyridin-3-yl)propanoate

Into a 250-mL round-bottom flask, was placed (2R,5S)-2-[(4,6-dichloropyridin-3-yl)methyl]-3,6-dimethoxy-5-(propan-2-yl)-2,5-dihydropyrazine (3.5 g, 9.66 mmol), hydrochloride acid (0.3M) (70 mL) and ACN (80 mL). The resulting solution was stirred for 2 h at 25° C. The reaction was then quenched by the addition of 100 mL of sodium bicarbonate (sat. aq.). The resulting mixture was extracted with 2×150 mL of DCM and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give methyl (2R)-2-amino-3-(4,6-dichloropyridin-3-yl)propanoate as colorless oil. MS: (ESI, m/z): 249, 251 [M+H]⁺.

Step 5. (2R)-2-Amino-3-(4,6-dichloropyridin-3-yl)propan-1-ol

Into a 250-mL round-bottom flask, was placed methyl (2R)-2-amino-3-(4,6-dichloropyridin-3-yl)propanoate (1.5 g, 5.72 mmol) and methanol (50 mL). NaBH₄ (690 mg, 18.24 mmol) was added in portion at 0° C. The resulting solution was stirred for 3 h at 25° C. The reaction was then quenched by the addition of water (20 mL). The resulting mixture was extracted with DCM (2×50 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:10 methanol/DCM) to afford (2R)-2-amino-3-(4,6-dichloropyridin-3-yl)propan-1-ol as a white solid. MS: (ESI, m/z): 221, 223 [M+H]⁺.

Step 6. (R)-7-Chloro-3,4-dihydro-2H-pyrano[3,2-c]pyridin-3-amine

Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed (2R)-2-amino-3-(4,6-dichloropyridin-3-yl)propan-1-ol (1 g, 4.30 mmo), sodium hydride (271 mg, 6.78 mmol, 60%) and DMSO (10 mL). The resulting solution was stirred for 16 h at 50° C. in an oil bath. After cooling to 25° C., the reaction was then quenched by the addition of water (20 mL). The resulting mixture was extracted with DCM (2×30 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by reverse phase chromatography (Column: C₁₈ silica gel; Mobile phase A: water (0.1% formic acid), B: ACN; Flow rate: 50 mL/min; Gradient: 0% B to 30% B in 30 min). The collected fraction was concentrated under vacuum to give (R)-7-chloro-3,4-dihydro-2H-pyrano[3,2-c]pyridin-3-amine as a white solid. MS: (ESI, m/z): 185, 187 [M+H]⁺.

Step 7. Benzyl (R)-(7-chloro-3,4-dihydro-2H-pyrano[3,2-c]pyridin-3-yl)carbamate

Into a 50-mL round-bottom flask, was placed (R)-7-chloro-3,4-dihydro-2H-pyrano[3,2-c]pyridin-3-amine (500 mg, 2.57 mmol, ethyl acetate (15 mL, 153.23 mmol), water (15 mL), benzyl chloroformate (558 mg, 3.27 mmol) and potassium carbonate (751 mg, 5.43 mmol). The resulting mixture was stirred for 30 min at 25° C. The resulting mixture was extracted with 3×20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:1 ethyl acetate/pet. ether) to afford benzyl (R)-(7-chloro-3,4-dihydro-2H-pyrano[3,2-c]pyridin-3-yl)carbamate as a white solid. MS: (ESI, m/z): 319, 321 [M+H]⁺.

Step 1. 3-(Bromomethyl)-2,6-dichloropyridine

Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed (2,6-dichloropyridin-3-yl)methanol (10 g, 56.17 mmol), DCM (200 mL) and PBr₃ (15.3 g, 56.52 mmol). The resulting solution was stirred for 30 min at 40° C. in an oil bath. The pH value of the solution was adjusted to 7 with NH₄HCO₃ (sat. aq.). The resulting mixture was extracted with 3×200 mL of DCM. The organic layers combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:10 to 1:5 ethyl acetate/pet. ether) to give 3-(bromomethyl)-2,6-dichloropyridine as an off-white solid. MS: (ESI, m/z): 240, 242, 244 [M+H]⁺.

Step 2. (2R,5S)-2-((2,6-Dichloropyridin-3-yl)methyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine

Into two 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed (2S)-3,6-dimethoxy-2-(propan-2-yl)-2,5-dihydropyrazine (2 g, 10.86 mmol) and THF (15 mL). This was followed by the addition of butyllithium (2.5 M) (6.5 mL, 16.25 mmol) at −78° C. The resulting solution was stirred for 30 min. To this was added 3-(bromomethyl)-2,6-dichloropyridine (2.62 g, 10.88 mmol). The resulting solution was stirred for an additional 1 h at −78° C. The reaction was then quenched by the addition of 5 mL of NH₄HCO₃ (saturated) and the mixture was diluted with 10 mL of H₂O. The resulting mixture of two batches was combined and extracted with 3×50 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with ⅕ ethyl acetate/pet. ether) to afford (2R,5S)-2-((2,6-dichloropyridin-3-yl)methyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine as a colorless oil. MS: (ESI, m/z): 344, 346 [M+H]⁺.

Step 3. Methyl (R)-2-amino-3-(2,6-dichloropyridin-3-yl)propanoate

Into a 500-mL round-bottom flask, was placed (2R,5S)-2-((2,6-dichloropyridin-3-yl)methyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (5.4 g, 16.35 mmol), acetonitrile (100 mL) and hydrochloric acid (0.3 N) (157 mL). The resulting solution was stirred for 1 hour at 24° C. The solvent was removed under vacuum and the residue was extracted with 3×100 mL of DCM. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:5 to 1:1 ethyl acetate/pet. ether) to afford to give methyl (R)-2-amino-3-(2,6-dichloropyridin-3-yl)propanoate as an off-white solid. MS: (ESI, m/z): 249, 251 [M+H]⁺.

Step 4. (R)-2-Amino-3-(2,6-dichloropyridin-3-yl)propan-1-ol

Into a 250-mL round-bottom flask, was placed methyl (R)-2-amino-3-(2,6-dichloropyridin-3-yl)propanoate (3.2 g, 12.85 mmol), methanol (15 mL), THF (60 mL) and NaBH₄ (1.46 g, 39.65 mmol). The resulting solution was stirred for 2 h at 24° C. The reaction was then quenched by the addition of 5 mL of water. The solvent was removed under vacuum. The residue was diluted with 50 mL of water. The resulting mixture was extracted with 3×50 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:20 methanol/DCM) to afford (R)-2-amino-3-(2,6-dichloropyridin-3-yl)propan-1-ol as an off-white solid. MS: (ESI, m/z): 221, 223 [M+H]⁺.

Step 5. (R)-7-Chloro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-3-amine

Into a 250-mL round-bottom flask fitted with a hydrogen balloon, was placed (R)-2-amino-3-(2,6-dichloropyridin-3-yl)propan-1-ol (2.6 g, 11.76 mmol) and DMSO (30 mL). This was followed by the addition of sodium hydride (706 mg, 29.42 mmol, 60%) at 0° C. The resulting solution was stirred at 24° C. for 30 min and then stirred overnight at 50° C. After cooling to 25° C., the reaction was then quenched by the addition of 60 mL of water. The resulting mixture was extracted with 3×60 mL of ethyl acetate. The organic layers combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by reverse phase chromatography (Column: C₁₈ silica gel; Mobile phase A: water (10 mM NH₄HCO₃), B: ACN; Flow rate: 50 mL/min; Gradient: 0% B to 30% B in 30 min). The collected fraction was concentrated under vacuum to give (R)-7-chloro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-3-amine as an off-white solid. MS: (ESI, m/z): 185, 187 [M+H]⁺.

Step 6. Benzyl (R)-(7-chloro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-3-yl)carbamate

Into a 100-mL round-bottom flask, was placed (R)-7-chloro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-3-amine (1.3 g, 6.34 mmol), ethyl acetate (15 mL), water (10 mL), potassium carbonate (1.95 g, 14.11 mmol) and benzyl chloroformate (1.44 g, 8.44 mmol). The resulting solution was stirred for 2 h at 25° C. The reaction was then quenched by the addition of 30 mL of water. The resulting mixture was extracted with 3×30 mL of ethyl acetate and the organic layers combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by re-crystallization from pet. ether. The solids were collected by filtration to give benzyl (R)-(7-chloro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-3-yl)carbamate as a white solid. MS: (ESI, m/z): 319, 321 [M+H]⁺.

Step 1. 7-Bromo-4-methyl-3-nitro-3,4-dihydro-2H-1-benzopyran

To a solution of 7-bromo-3-nitro-2H-chromene (2.2 g, 8.59 mmol) in THF (30 mL) was added CH₃MgBr (1 M in THF) (13 mL, 13.00 mmol) at −78° C. The resulting solution was stirred for 20 min at −78° C. The reaction was then quenched by the addition of 20 mL of saturated aqueous NH₄C₁ solution. The resulting mixture was extracted with 3×50 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 3:1 pet. ether/ethyl acetate) to afford 7-bromo-4-methyl-3-nitro-3,4-dihydro-2H-1-benzopyran as yellow oil. GCMS: (ESI, m/z): 271, 273 [M+H]⁺.

Step 2. 7-Bromo-4-methyl-3,4-dihydro-2H-1-benzopyran-3-amine

To a solution of BH₃-THF (1M) (40 mL, 40.00 mmol) and NaBH₄ (1.26 g, 33.30 mmol) in THF (40 mL) was added 7-bromo-4-methyl-3-nitro-3,4-dihydro-2H-1-benzopyran (900 mg, 3.31 mmol). The resulting mixture was stirred in a sealed tube for 16 h at 75° C. Then methanol (40 mL) was added and the reaction mixture was stirred for 6 h at 80° C. After cooling to 25° C., the solvent was removed under vacuum. The residue was diluted with 50 mL of ice/water. The resulting mixture was extracted with 3×50 of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by reverse phase chromatography (Column: C₁₈ silica gel; Mobile phase A: water (0.05% TFA), B: ACN; Gradient: 0% B to 40% over 45 min) to afford 7-bromo-4-methyl-3,4-dihydro-2H-1-benzopyran-3-amine as a white solid. MS: (ESI, m/z): 242, 244 [M+H]⁺.

Step 3. Benzyl N-(7-bromo-4-methyl-3,4-dihydro-2H-1-benzopyran-3-yl) carbamate

A solution of 7-bromo-4-methyl-3,4-dihydro-2H-1-benzopyran-3-amine (500 mg, 2.07 mmol) and CbzCl (423 mg, 2.48 mmol) in ethyl acetate (8 mL) and a solution of potassium carbonate (567 mg, 4.10 mmol) in water (8 mL) was stirred for 1 h at 25° C. The resulting solution was diluted with 20 mL of water. The resulting mixture was extracted with 3×20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 3:1 pet. ether/ethyl acetate) to afford benzyl N-(7-bromo-4-methyl-3,4-dihydro-2H-1-benzopyran-3-yl)carbamate as a white solid. MS: (ESI, m/z): 376, 378 [M+H]⁺.

Step 1. 1,4-Dibenzyl-1,4-diazepan-6-ol

A solution of 1,3-dibromopropan-2-ol (12.37 g, 56.77 mmol), benzyl(2-(benzylamino)ethyl)amine (13.56 g, 56.42 mmol), and Et₃N (17.17 g, 169.68 mmol) in toluene (50 mL) was stirred for 48 h at 120° C. After cooling to 25° C., the reaction was then quenched by the addition of 100 mL of water. The resulting mixture was extracted with 2×100 mL of ethyl acetate and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:2 ethyl acetate/pet. ether) to afford 1,4-dibenzyl-1,4-diazepan-6-ol as yellow oil. MS: (ESI, m/z): 297 [M+H]⁺.

Step 2. 1,4-Dibenzyl-6-((tert-butyldimethylsilyl)oxy)-1,4-diazepane

A solution of 1,4-dibenzyl-1,4-diazepan-6-ol (2.0 g, 6.61 mmol), imidazole (900 mg, 13.22 mmol) and TBS-C₁ (1.2 g, 7.96 mmol) in DMF (10 mL) was stirred for 16 h at 25° C. The reaction was then quenched by the addition of 50 mL of water. The resulting mixture was extracted with 2×50 mL of ethyl acetate and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:5 ethyl acetate/pet. ether) to afford 1,4-dibenzyl-6-((tert-butyldimethylsilyl)oxy)-1,4-diazepane as yellow oil. MS: (ESI, m/z): 411 [M+H]⁺.

Step 3. 6-((tert-Butyldimethylsilyl)oxy)-1,4-diazepane

A mixture of 1,4-dibenzyl-6-((tert-butyldimethylsilyl)oxy)-1,4-diazepane (1.5 g, 3.47 mmol) and Pd(OH)₂ on carbon (20 mg, 10%) in ethyl acetate (10 mL) was stirred under an atmosphere of hydrogen for 28 h at 20° C. The solids were filtered out. The filtrate was concentrated under vacuum to afford 6-((tert-butyldimethylsilyl)oxy)-1,4-diazepane as colorless oil. MS: (ESI, m/z): 231 [M+H]⁺.

Step 4. Tert-Butyl 6-((tert-butyldimethylsilyl)oxy)-1,4-diazepane-1-carboxylate

A solution of 6-((tert-butyldimethylsilyl)oxy)-1,4-diazepane (1.2 g, 4.95 mmol), Boc₂O (700 mg, 3.21 mmol), and triethylamine (500 mg, 4.94 mmol) in DCM (20 mL) was stirred for 2 h at −40° C. in a dry ice/ethanol bath and stirred for an additional 1 h at 20° C. The reaction was then quenched by the addition of 40 mL of water. The resulting mixture was extracted with 2×40 mL of ethyl acetate and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:10 methanol/DCM) to afford tert-butyl 6-((tert-butyldimethylsilyl)oxy)-1,4-diazepane-1-carboxylate as colorless oil. MS: (ESI, m/z): 331 [M+H]⁺.

To a solution of tert-butyl 2-(hydroxymethyl)piperazine-1-carboxylate (1 g, 4.39 mmol) and triethylamine (1.53 mL, 10.98 mmol) in DCM (20 mL) was added tert-butyl(chloro)dimethylsilane (693 mg, 4.60 mmol). The resulting solution was stirred overnight at 20° C. The reaction was then quenched by the addition of 20 mL of water. The resulting mixture was extracted with 3×20 mL of DCM. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 20:1 ethyl DCM/methanol) to afford tert-butyl 6-((tert-butyldimethylsilyl)oxy)-1,4-diazepane-1-carboxylate as an off-colorless oil. MS: (ESI, m/z): 331 [M+H]⁺.

Intermediate 47-1. Benzyl N-[2-[(trifluoromethane)sulfonyloxy]-5,6,7,8-tetrahydroquinolin-6-yl]carbamate Intermediate 47-2. Benzyl N-[(6S)-2-(trifluoromethanesulfonyloxy)-5,6,7,8-tetrahydroquinolin-6-yl]carbamate Intermediate 47-3. Benzyl N-[(6R)-2-(trifluoromethanesulfonyloxy)-5,6,7,8-tetrahydroquinolin-6-yl]carbamate

Step 1

A solution of 1,4-dioxaspiro[4.5]decan-8-one (50.0 g, 320 mmol), ethyl prop-2-ynoate (68 mL, 672 mmol) and a solution of NH₃ in MeOH (230 mL, 7M) in isopropanol (1.3 L) was stirred for 14 h at 130° C. The reaction mixture was cooled to 20° C. The solvent was removed under vacuum. The solids were collected by filtration. The cake was washed with 2×30 mL of pet. ether and dried under vacuum to give 7′,8′-dihydro-5′H-spiro[1,3-dioxolane-2,6′-quinoline]-2′-ol as an off-white solid. MS (ESI, m/z): 208 [M+H]⁺.

Step 2. 7′,8′-Dihydro-5′H-spiro[1,3-dioxolane-2,6′-quinoline]-2′-yl trifluoromethanesulfonate

To a solution of 7′,8′-dihydro-5′H-spiro[1,3-dioxolane-2,6′-quinoline]-2′-ol (24.0 g, 116 mmol) and triethylamine (64.4 mL, 464 mmol) in DCM (500 mL) was added a solution of trifluoromethanesulfonic anhydride (58.4 mL, 347 mmol) in DCM (100 mL) at 10° C. The resulting solution was stirred for 1 h at 20° C. The mixture was concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 3:1 ethyl acetate/pet. ether) to afford 7′,8′-dihydro-5′H-spiro[1,3-dioxolane-2,6′-quinoline]-2′-yl trifluoromethanesulfonate as a yellow oil. MS (ESI, m/z): 340 [M+H]⁺.

Step 3. 6-Oxo-5,6,7,8-tetrahydroquinolin-2-yl trifluoromethanesulfonate

A solution of 7′,8′-dihydro-5′H-spiro[1,3-dioxolane-2,6′-quinoline]-2′-yl trifluoromethanesulfonate (35.0 g, 103 mmol) and hydrochloric acid (206 mL, 1N) in acetone (300 mL) was stirred for 1 h at 75° C. The mixture was cooled to 20° C. The acetone was concentrated under vacuum. The pH value of the residue was adjusted to 7-8 with NaHCO₃ (sat., aq.). The resulting mixture was extracted with 3×100 mL of DCM. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by recrystallization with 100 mL of the mixture solvent of ethyl acetate and pet. ether (10:1) to give 6-oxo-5,6,7,8-tetrahydroquinolin-2-yl trifluoromethanesulfonate as an off-white solid. MS (ESI, m/z): 296 [M+H]⁺.

Step 4. 6-Amino-5,6,7,8-tetrahydroquinolin-2-yl trifluoromethanesulfonate

A mixture of 6-oxo-5,6,7,8-tetrahydroquinolin-2-yltrifluoromethanesulfonate (16.0 g, 54.2 mmol) and NH₄OAc (50.1 g, 650 mmol) in methanol (250 mL) was stirred for 1 h at 20° C. NaBH₃CN (4.10 g, 65.2 mmol) was added in portions at 10° C. The resulting mixture was allowed to react for 13 h at 20° C. The reaction was then quenched by the addition of 50 mL of water/ice. The solvent was concentrated under vacuum. The residue was diluted with 100 mL of hydrochloric acid (1N). The resulting mixture was extracted with 2×100 mL of DCM. The pH value of aqueous phase was adjusted to 10 with Na₂CO₃ (sat., aq.). The aqueous phase was extracted with 4×100 mL of DCM. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give 6-amino-5,6,7,8-tetrahydroquinolin-2-yl trifluoromethanesulfonate as a yellow oil. MS (ESI, m/z): 297 [M+H]⁺.

Step 5. Benzyl N-[2-[(trifluoromethane)sulfonyloxy]-5,6,7,8-tetrahydroquinolin-6-yl]carbamate

A mixture of 6-amino-5,6,7,8-tetrahydroquinolin-2-yl trifluoromethanesulfonate (12.0 g, 40.5 mmol), potassium carbonate (14.0 g, 101 mmol) and CbzCl (7.4 mL, 52.8 mmol) in ethyl acetate (100 mL) was stirred for 2 h at 20° C. The reaction was then quenched by the addition of 100 mL of water/ice. The mixture was extracted with 3×100 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by recrystallization with 80 mL of the mixture solvent of ethyl acetate and pet. ether (10:1) to give benzyl N-[2-[(trifluoromethane)sulfonyloxy]-5,6,7,8-tetrahydroquinolin-6-yl]carbamate as an off-white solid. MS (ESI, m/z): 431 [M+H]⁺.

Step 6. Benzyl N-[(6S)-2-(trifluoromethanesulfonyloxy)-5,6,7,8-tetrahydroquinolin-6-yl]carbamate and benzyl N-[(6R)-2-(trifluoromethanesulfonyloxy)-5,6,7,8-tetrahydroquinolin-6-yl]carbamate

The racemate benzyl N-[2-(trifluoromethanesulfonyloxy)-5,6,7,8-tetrahydroquinolin-6-yl]carbamate (Intermediate 47-1) (7.00 g, 16.3 mmol) was separated by SFC (Column: Chiralpak AD-H SFC, 5×25 cm, 5 μm; Mobile Phase, A: CO₂: 55% and B: MeOH: 45%; Flow rate: 150 mL/min). The first eluting isomer (RT=4.23 min) was collected and concentrated under vacuum to give benzyl N-[(6S)-2-(trifluoromethanesulfonyloxy)-5,6,7,8-tetrahydroquinolin-6-yl]carbamate (Intermediate 47-2) as an off-white solid. And the second eluting isomer (RT=5.16 min) was collected and concentrated under vacuum to give benzyl N-[(6R)-2-(trifluoromethanesulfonyloxy)-5,6,7,8-tetrahydroquinolin-6-yl]carbamate (Intermediate 47-3) as an off-white solid. MS (ESI, m/z) for both isomers: 431 [M+H]⁺.

Intermediate 47-2. Benzyl N-[(6S)-2-(trifluoromethanesulfonyloxy)-5,6,7,8-tetrahydroquinolin-6-yl]carbamate

Step 1. (S)-6-Amino-5,6,7,8-tetrahydroquinolin-2-yl trifluoromethanesulfonate

A solution of 6-amino-5,6,7,8-tetrahydroquinolin-2-yl trifluoromethanesulfonate (183 g, 525.65 mmol) and L-(−)-mandelic acid (39.99 g, 262.83 mmol) in EtOH (1830 mL) was stirred at 70° C. for 2 h. The mixture was allowed to cool down to 25° C. slowly and stirred for overnight. The precipitate that was formed was collected by filtration and dried under vacuum to afford the chiral salt as a white solid. The salt was dissolved in H₂O (350 mL) and the pH value of aqueous phase was adjusted to 12-14 with NaOH (1 N, aq). The aqueous phase was extracted with EtOAc (500 mL). The organic layer was dried over Na₂SO₄, filtered and concentrated under vacuum to afford the free base of the chiral amine (S)-6-amino-5,6,7,8-tetrahydroquinolin-2-yl trifluoromethanesulfonate as a yellow oil. MS (ESI, m/z): 297 [M+H]⁺. ¹H NMR (DMSO-d₆, 400 mHz) δ (ppm): 7.79 (d, J=8.0 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 3.14-3.11 (m, 1H), 2.97-2.81 (m, 3H), 2.54-2.52 (m, 1H), 2.61-2.58 (m, 2H), 1.64-1.59 (m, 1H).

Step 2. Benzyl N-[(6S)-2-(trifluoromethanesulfonyloxy)-5,6,7,8-tetrahydroquinolin-6-yl]carbamate

To a solution of (S)-6-amino-5,6,7,8-tetrahydroquinolin-2-yl trifluoromethanesulfonate (48.0 g, 162.02 mmol) and K₂CO₃ (55.98 g, 405.04 mmol) in EtOAc (480 mL) was added drop-wise CbzCl (35.93 g, 210.62 mmol, 29.94 mL) at 0° C. The mixture was stirred at 20° C. for 30 min. The reaction was then quenched by water/ice (150 mL). The mixture was extracted with ethyl acetate (350 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude was triturated with pet. ether (200 mL) at 20° C. The resulting precipitate was collected by filtration and dried under vacuum to afford benzyl N-[(65)-2-(trifluoromethanesulfonyloxy)-5,6,7,8-tetrahydroquinolin-6-yl]carbamate as a pale pink solid. MS (ESI, m/z): 431 [M+H]⁺. ¹H NMR (DMSO-d₆, 400 mHz) δ (ppm): 7.82 (d, J=8.0 Hz, 1H), 7.49 (m, 1H), 7.37-7.28 (m, 6H), 5.04 (s, 2H), 3.82 (m, 1H), 3.08 (dd, J=16.8 Hz, 4.8 Hz, 1H), 2.91-2.88 (m, 2H), 2.76-2.72 (m, 1H), 2.02-2.00 (m, 1H), 1.83-1.75 (m, 1H).

The following intermediate in Table 7 was prepared using standard chemical manipulations and procedures similar to those used for the preparation of Intermediate 47-1.

TABLE 7 LRMS Intermediate m/z Number Structure and Name [M + H]⁺ 47-4¹

  benzyl N[2′- (trifluoromethanesulfonyloxy)- 6′,7′-dihydro-5′H- spiro[cyclopropane-1,8′- quinolin]-6′-yl]carbamate 457 ¹Notes on procedures: In Step 1, the ketone used was 6,9-dioxadispiro[2.1.4⁵.3³]dodecan-12-one, which was prepared by the following method: (2-chloroethyl)dimethylsulfonium iodide (88.0 g, 347 mmol) was slowly added to a solution of 1,4-dioxaspiro[4.5]decan-8-one (60.0 g, 384 mmol) and t-BuOK (88.0 g, 784 mmol) in t-BuOH (1.50 L) over 4 h. The resulting solution was stirred for 1 h at 25° C. The solids were filtered. The filtrate was concentrated under vacuum. The residue was diluted with water (400 mL). The resulting mixture was extracted with DCM (3 × 400 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified via reverse phase chromatography to afford 6,9-dioxadispiro[2.1.4⁵.3³]dodecan-12-one as a pale yellow oil. MS (ESI, m/z): 183 [M + H]⁺.

Intermediate 48-1. Cis-tert-Butyl N-[4-(methoxymethyl)pyrrolidin-3-yl]carbamate Intermediate 48-2. Tert-Butyl N-[(3R,4R)-4-(methoxymethyl)pyrrolidin-3-yl]carbamate and

Step 1. Cis-Benzyl 3-[[(tert-butoxy)carbonyl]amino]-4-(hydroxymethyl)pyrrolidine-1-carboxylate

A solution of cis-benzyl 3-amino-4-(hydroxymethyl)pyrrolidine-1-carboxylate (2.00 g, 7.99 mmol), Et₃N (2.13 mL, 23.7 mmol) and (Boc)₂O (2.20 g, 10.1 mmol) in THF (40 mL) and water (20 mL) was stirred for 2 h at 20° C. The solvent was removed under vacuum. The residue was diluted with water (20 mL). The resulting mixture was extracted with ethyl acetate (3×20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by a silica gel chromatography (eluting with 1:3 ethyl acetate/pet. ether) to give cis-benzyl 3-[[(tert-butoxy)carbonyl]amino]-4-(hydroxymethyl)pyrrolidine-1-carboxylate as an off-white solid. MS (ESI, m/z): 351 [M+H]⁺.

Step 2. Cis-Benzyl 3-[[(tert-butoxy)carbonyl]amino]-4-(methoxymethyl)pyrrolidine-1-carboxylate

A solution of trimethyloxoniumtetrafluoroborate (1.50 g, 10.4 mmol) in DCM (20 mL) was added to a stirring solution of 1,8-bis(dimethylamino)naphthalene (2.20 g, 10.3 mmol) and cis-benzyl 3-[[(tert-butoxy)carbonyl]amino]-4-(hydroxymethyl)pyrrolidine-1-carboxylate (2.20 g, 6.09 mmol) in DCM (100 mL). The resulting mixture was stirred for 3 h at 40° C. The pH of the mixture was adjusted to 4-6 with HCl (3N, aq.). The resulting mixture was extracted with ethyl acetate (3×100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:1 ethyl acetate/pet. ether) to afford cis-benzyl 3-[[(tert-butoxy)carbonyl]amino]-4-(methoxymethyl)pyrrolidine-1-carboxylate as white solid. MS (ESI, m/z): 365 [M+H]⁺.

Step 3. Cis-tert-Butyl N-[4-(methoxymethyl)pyrrolidin-3-yl]carbamate

A mixture of cis-benzyl 3-[[tert-butoxy)carbonyl]amino]-4-(methoxymethyl)pyrrolidine-1-carboxylate (1.00 g, 2.74 mmol) and palladium on carbon (1.00 g, 10%) in ethyl acetate (50 mL) was stirred for 1 h at 20° C. under a hydrogen atmosphere (balloon). The solids were filtered out. The filtrate was concentrated under vacuum to give cis-tert-butyl N-[4-(methoxymethyl)pyrrolidin-3-yl]carbamate (Intermediate 48-1) as yellow oil (crude). MS (ESI, m/z): 231 [M+H]⁺.

Step 4. Tert-Butyl N-[(3R,4R)-4-(methoxymethyl)pyrrolidin-3-yl]carbamate

The racemate cis-benzyl 3-[[(tert-butoxy)carbonyl]amino]-4-(methoxymethyl)pyrrolidine-1-carboxylate was separated into its enantiomers by SFC (Column: Chiralpak IA-SFC, 5×25 cm, 5 μm; Mobile Phase, A: CO₂: 70% and B: MeOH (containing 2 mM NH₃ in MeOH): 30%; Flow rate: 150 mL/min). The first eluting isomer (RT=3.91 min) was collected and concentrated under vacuum to give benzyl (3S,4S)-3-[[(tert-butoxy)carbonyl]amino]-4-(methoxymethyl)pyrrolidine-1-carboxylate as a yellow solid. The second eluting isomer (RT=5.04 min) was collected and concentrated under vacuum to give benzyl (3R,4R)-3-[[(tert-butoxy)carbonyl]amino]-4-(methoxymethyl)pyrrolidine-1-carboxylate (Intermediate 48-3) as a yellow solid. MS (ESI, m/z): 365 [M+H]⁺.

A mixture of benzyl (3R,4R)-3-[[(tert-butoxy)carbonyl]amino]-4-(methoxymethyl)pyrrolidine-1-carboxylate (Intermediate 48-3) (0.800 g, 2.20 mmol) and palladium on carbon (0.800 g, 10%) in ethyl acetate (30 mL) was stirred for 1 h at 25° C. under a hydrogen atmosphere (balloon). The solids were filtered out. The filtrate was concentrated under vacuum to give tert-butyl N-[(3R,4R)-4-(methoxymethyl)pyrrolidin-3-yl]carbamate (Intermediate 48-2) as a yellow oil (crude). MS (ESI, m/z): 231 [M+H]⁺.

Intermediate 48-3. Benzyl (3R,4R)-3-[[(tert-butoxy)carbonyl]amino]-4-(methoxymethyl)pyrrolidine-1-carboxylate

Step 1. Benzyl N-(2,2-dimethoxyethyl)carbamate

A solution of 2,2-dimethoxyethan-1-amine (1600 g, 15.22 mol) in toluene (8 L), was added a solution of NaOH (858 g, 21.45 mol) in water (4.42 L). This was followed by the addition of CbzCl (2598 g, 15.23 mol) dropwise with stirring at <20° C. The resulting solution was stirred for 4 h at room temperature. The organic layer was separated and washed with 3×5 L of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to afford benzyl N-(2,2-dimethoxyethyl)carbamate as a white solid.

Step 2. Benzyl N-(2,2-dimethoxyethyl)-N-(prop-2-en-1-yl)carbamate

To a solution of benzyl N-(2,2-dimethoxyethyl)carbamate (1700 g, 7.10 mol), KOH (1755 g, 31.28 mol) and benzyltriethylammonium chloride (32.37 g, 142.1 mmol) in toluene (7.82 L) was added 3-bromoprop-1-ene (1117.4 g, 9.24 mol) dropwise with stirring at room temperature. The resulting solution was stirred for 24 h at room temperature. Two batches were thus run in parallel. The reaction was then quenched by the addition of 10 L of water. The resulting solution was extracted with 2×7 L of toluene and the organic layers combined. The organic phase was washed with 2×10 L of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to afford benzyl N-(2,2-dimethoxyethyl)-N-(prop-2-en-1-yl)carbamate as pale yellow oil.

Step 3. Benzyl N-(2-oxoethyl)-N-(prop-2-en-1-yl)carbamate

A solution of benzyl N-(2,2-dimethoxyethyl)-N-(prop-2-en-1-yl)carbamate (3900 g, 13.96 mol) in 88% formic acid (5460 mL) was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was diluted with 20 L of ethyl acetate, washed with 4×10 L of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum to afford benzyl N-(2-oxoethyl)-N-(prop-2-en-1-yl)carbamate as brown oil.

Step 4. Benzyl N-[2-(hydroxyimino)ethyl]-N-(prop-2-en-1-yl)carbamate

To a solution of benzyl N-(2-oxoethyl)-N-(prop-2-en-1-yl)carbamate (1700 g, 7.29 mol) and NH₂OH—HCl (638 g, 9.18 mol) in ACN (9.52 L) was added a solution of NaOAc (669 g, 8.16 mol) in H₂O (4.96 L). The resulting solution was stirred for 20 h at room temperature. Two batches were thus run in parallel. The resulting mixture was concentrated under vacuum and extracted with 3×10 L of ethyl acetate and the organic layers combined. The organic phase was washed with 3×5 L of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by silica gel chromatography (eluting with 1:9 EtOAc/pet. ether) to afford benzyl N-[2-(hydroxyimino)ethyl]-N-(prop-2-en-1-yl)carbamate as colorless oil.

Step 5. Cis-Benzyl 3-amino-4-(hydroxymethyl)pyrrolidine-1-carboxylate

A solution of benzyl N-[2-(hydroxyimino)ethyl]-N-(prop-2-en-1-yl)carbamate (1200 g, 4.83 mol) and xylene (6 L) was stirred overnight at 130° C. The mixture was cooled to room temperature. HOAc (6 L) was added to the mixture. Then Zn (1200 g, 18.35 mol) was added into the mixture at 15° C. The resulting solution was stirred overnight at room temperature in a water bath. Two batches were thus run in parallel. The batches were combined and filtered. The filtered cake was washed with xylene. The combined filtrate was diluted with 20 L of water. The mixture was extracted with xylene (4×5 L). The aqueous phase was concentrated under vacuum. The pH value of the residue was adjusted to 9-10 with saturated sodium carbonate. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was extracted with 5 L of THF and concentrated under vacuum to afford cis-benzyl 3-amino-4-(hydroxymethyl)pyrrolidine-1-carboxylate as brown oil.

Step 6. Cis-Benzyl 3-[[(tert-butoxy)carbonyl]amino]-4-(hydroxymethyl)pyrrolidine-1-carboxylate

To a solution of cis-benzyl 3-amino-4-(hydroxymethyl)pyrrolidine-1-carboxylate (900 g, 3.60 mol) and triethylamine (728 g, 7.19 mol) in methanol (9 L) was added di-tert-butyl dicarbonate (863 g, 3.95 mol) dropwise with stirring at room temperature. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by silica gel chromatography (eluting with 2:3 EtOAc/pet. ether) to afford cis-benzyl 3-[[tert-butoxy)carbonyl]amino]-4-(hydroxymethyl)pyrrolidine-1-carboxylate as a white solid.

Step 7. Cis-Benzyl 3-[[(tert-butoxy)carbonyl]amino]-4-(methoxymethyl)pyrrolidine-1-carboxylate

To a mixture of cis-benzyl 3-[[(tert-butoxy)carbonyl]amino]-4-(hydroxymethyl)pyrrolidine-1-carboxylate (600 g, 1.71 mol) and 2,6-di-tert-butyl-4-methylpyridine (1406 g, 6.85 mol) in DCM (12 L) was added trimethyloxonium tetrafluoroborate (506.5 g, 3.42 mol). The reaction was stirred overnight at room temperature. The resulting solution was concentrated under vacuum. The crude product was purified by silica gel chromatography (eluting with 3:7 EtOAc/pet. ether) to afford cis-benzyl 3-[[tert-butoxy)carbonyl]amino]-4-(methoxymethyl)pyrrolidine-1-carboxylate as a white solid.

Step 8. Benzyl (3R,4R)-3-[[(tert-butoxy)carbonyl]amino]-4-(methoxymethyl)pyrrolidine-1-carboxylate

The racemate cis-benzyl 3-[[(tert-butoxy)carbonyl]amino]-4-(methoxymethyl)pyrrolidine-1-carboxylate was separated into its enantiomers by SFC (Column: Lux 5 μm Amylose-1, 5×25 cm, 5 μm; Mobile Phase A: CO₂: 50%, and B: MeOH: 50%; Flow rate: 160 mL/min). The first eluting isomer (RT=4.2 min) was collected and concentrated under vacuum to give benzyl (3S,4S)-3-[[(tert-butoxy)carbonyl]amino]-4-(methoxymethyl)pyrrolidine-1-carboxylate as a white solid. MS (ESI, m/z): 387 [M+Na]⁺ ¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.31-7.44 (m, 5H), 5.14-5.36 (m, 3H), 4.28 (s, 1H), 3.46-3.70 (m, 4H), 3.32-3.46 (m, 5H), 2.54 (s, 1H), 1.47 (s, 9H).

The second eluting isomer (RT=5.7 min) was collected and concentrated under vacuum to give benzyl (3R,4R)-3-[[(tert-butoxy)carbonyl]amino]-4-(methoxymethyl)pyrrolidine-1-carboxylate (Intermediate 48-3) as a white solid. MS (ESI, m/z): 387 [M+Na]⁺ ¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.33-7.40 (m, 5H), 5.09-5.40 (m, 3H), 4.28 (s, 1H), 3.46-3.73 (m, 4H), 3.32-3.46 (m, 5H), 2.53-5.55 (m, 1H), 1.46 (s, 9H).

Step 1. Benzyl (3S,4S)-3-azido-4-(methoxy-d3)pyrrolidine-1-carboxylate

To a solution of benzyl (3S,4S)-3-azido-4-hydroxypyrrolidine-1-carboxylate (202.7 mg, 0.773 mmol) in anhydrous DMF (5 mL) was added NaH (60% dispersion in mineral oil, 37.1 mg, 0.927 mmol). The reaction was allowed to stir at room temperature for 1 h. Then, iodomethane-d3 (0.058 ml, 0.927 mmol) was added and the reaction was stirred at 22° C. for 6 h. The reaction was diluted with 5 mL of EtOAc and washed with 2×3 mL of H₂O. The organic layer was separated, dried over anhydrous Na₂SO₄, filtered, and concentrated to afford crude benzyl (3S,4S)-3-azido-4-(methoxy-d3)pyrrolidine-1-carboxylate as a yellow oil. MS: (ESI, m/z): 280 [M+H]⁺.

Step 2. Benzyl (3S,4S)-3-amino-4-(methoxy-d3)pyrrolidine-1-carboxylate

A solution of benzyl (3S,4S)-3-azido-4-(methoxy-d3)pyrrolidine-1-carboxylate (215.8 mg, 0.773 mmol) and triphenylphosphine (223 mg, 0.850 mmol) in THF (1.405 mL) and water (0.14 mL) was stirred for 1 h at room temperature. The reaction was then heated at 50° C. for 5 h. After cooling to room temperature, the reaction was concentrated under vacuum. The residue was purified by prep-HPLC (Column: Waters)(Bridge Prep C18 OBD 5 μm, 19×50 mm; Mobile Phase gradient 0% to 35% ACN, 0.1% formic acid over 8 min; Flow rate: 23 mL/min) to afford benzyl (3S,4S)-3-amino-4-(methoxy-d3)pyrrolidine-1-carboxylate as a colorless oil. MS: (ESI, m/z): 254 [M+H]⁺.

Step 3. Benzyl (3S,4S)-3-((tert-butoxycarbonyl)amino)-4-(methoxy-d3)pyrrolidine-1-carboxylate

A solution of benzyl (3S,4S)-3-amino-4-(methoxy-d3)pyrrolidine-1-carboxylate (217 mg, 0.858 mmol), Et₃N (225 μl, 1.61 mmol), and Boc₂O (0.299 mL, 1.29 mmol) in THF (1.43 mL) and water (1.43 mL) was stirred for 30 min at room temperature. The resulting mixture was extracted with 2×30 mL of DCM. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to afford benzyl (3S,4S)-3-((tert-butoxycarbonyl)amino)-4-(methoxy-d3)pyrrolidine-1-carboxylate as a colorless oil. MS: (ESI, m/z): 354 [M+H]⁺.

Step 4. Tert-Butyl ((3S,4S)-4-(methoxy-d3)pyrrolidin-3-yl)carbamate

A mixture of benzyl 3-((tert-butoxycarbonyl)amino)-4-methoxypyrrolidine-1-carboxylate (200 mg, 0.57 mmol) and Pd/C (200 mg, 10%) in EtOAc (10 mL) was stirred for 3 h at room temperature under an atmosphere of hydrogen. The solids were filtered out and washed with 3×10 mL of EtOAc. The filtrate was concentrated under vacuum to afford tert-butyl N-(4-methoxypyrrolidin-3-yl)carbamate as a colorless oil. MS: (ESI, m/z): 220 [M+H]⁺. ¹H NMR (CDCl₃, 300 MHz) δ (ppm): 8.04-8.26 (m, 1H), 4.41-4.86 (m, 1H), 3.93-4.22 (m, 1H), 3.09-3.92 (m, 3H), 1.46 (s, 9H).

Step 1. 4-Chloro-3,5-difluoro-2-hydroxybenzaldehyde

A solution of 3-chloro-2,4-difluorophenol (4.00 g, 23.6 mmol) and HMTA (6.60 g, 47.2 mmol) in TFA (60 mL) was stirred for 3 h at 100° C. After cooling to 0° C., conc. H₂SO₄ (10 mL) and H₂O (50 mL) were added into the mixture at 0° C. The mixture was stirred for 2 h at 20° C. and then diluted with H₂O (40 mL). The pH value of the mixture was adjusted to 7-8 with dibutylamine. The resulting mixture was extracted with ethyl acetate (3×100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:5 ethyl acetate/pet. ether) to afford 4-chloro-3,5-difluoro-2-hydroxybenzaldehyde as an off-white solid. GCMS (ESI, m/z): 192,194 [M+H]⁺.

Step 2. 7-Chloro-6,8-difluoro-3-nitro-2H-chromene

2-Nitroethan-1-ol (3.72 mL, 51.9 mmol) was added to a stirring solution of 4-chloro-3,5-difluoro-2-hydroxybenzaldehyde (1.50 g, 7.77 mmol), dibutylamine (0.659 mL, 3.89 mmol) and phthalic anhydride (2.20 g, 14.8 mmol) in toluene (80 mL) via an injection pump with the flowrate of 0.5 mL/h at 125° C. The resulting solution was refluxed for 16 h at 125° C. After cooling to 20° C., the resulting mixture was concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:10 ethyl acetate/pet. ether) to give 7-chloro-6,8-difluoro-3-nitro-2H-chromene as a yellow solid. MS (ESI, m/z): 248, 250 [M+H]⁺.

Step 3. 7-Chloro-8-fluoro-3,4-dihydro-2H-1-benzopyran-3-amine

A mixture of 7-chloro-6,8-difluoro-3-nitro-2H-chromene (1.30 g, 5.25 mmol), BH₃ (40 mL, 1M in THF), and NaBH₄ (399 mg, 10.5 mmol) was stirred for 16 h at 65° C. MeOH (80 mL) was added into the mixture slowly at <10° C. The resulting solution was stirred for 8 h at 80° C. After cooling to 20° C., the resulting mixture was concentrated under vacuum. The residue was purified via reverse phase chromatography (Column: C₁₈ silica gel; Mobile phase, A: water (10 mM NH₄HCO₃) and B: ACN (5% to 75% in 20 min)) to afford 7-chloro-8-fluoro-3,4-dihydro-2H-1-benzopyran-3-amine as an off-white solid. MS (ESI, m/z): 220, 222 [M+H]⁺.

Step 4. Benzyl N-(7-chloro-6,8-difluoro-3,4-dihydro-2H-1-benzopyran-3-yl)carbamate

CbzCl (0.500 mL, 3.55 mmol) was added to a mixture of 7-chloro-6,8-difluoro-3,4-dihydro-2H-1-benzopyran-3-amine (650 mg, 2.96 mmol) and potassium carbonate (822 mg, 5.92 mmol) in ethyl acetate (20 mL) and water (20 mL) at <10° C. The resulting solution was then stirred for 1 h at 25° C. and diluted with water (30 mL). The resulting mixture was extracted with ethyl acetate (3×30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:5 ethyl acetate/pet. ether) to afford benzyl N-(7-chloro-6,8-difluoro-3,4-dihydro-2H-1-benzopyran-3-yl)carbamate as an off-white solid. MS (ESI, m/z): 354, 356 [M+H]⁺.

Intermediate 51-1. Tert-Butyl N-[(3R,4S)-4-(difluoromethyl)pyrrolidin-3-yl]carbamate

Step 1. Ethyl 4,4-difluoro-3-hydroxybutanoate

NaBH₄ (34.2 g, 902 mmol) was added into a stirring solution of ethyl 4,4-difluoro-3-oxobutanoate (100 g, 602 mmol) in toluene (1 L) at 0° C. The resulting mixture was stirred for 2 h at 0° C., and then warmed up to 25° C. and stirred for 16 h. The reaction was quenched with water (400 mL). The resulting mixture was extracted with ethyl acetate (2×1 L). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford ethyl 4,4-difluoro-3-hydroxybutanoate as a light yellow oil. GCMS (ESI, m/z): 168 [M+H]⁺.

Step 2. Ethyl (2E)-4,4-difluorobut-2-enoate

To a solution of ethyl 4,4-difluoro-3-hydroxybutanoate (40.0 g, 238 mmol) and Et₃N (99.0 mL, 712 mmol) in DCM (300 mL) was added MSCl (28.0 mL, 244 mmol) dropwise at 0° C. The resulting mixture was warmed to 25° C. and stirred for 16 h. The reaction was quenched with water (500 mL). The resulting mixture was extracted with DCM (2×500 mL). The organic layers were combined, washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:10 ethyl acetate/pet. ether) to afford ethyl (2E)-4,4-difluorobut-2-enoate as a yellow green oil. GCMS (ESI, m/z): 150 [M+H]⁺.

Step 3. trans-Ethyl 1-benzyl-4-(difluoromethyl)pyrrolidine-3-carboxylate

To a stirring solution of ethyl (2E)-4,4-difluorobut-2-enoate (12.0 g, 79.9 mmol) and benzyl(methoxymethyl)[(trimethylsilyl)methyl]amine (30.7 mL, 120 mmol) in DCM (250 mL) was added a solution of TFA (0.59 mL, 5.21 mmol) in DCM (20 mL) dropwise over 2 min at 0° C. The resulting mixture was warm to 25° C. and was stirred for 14 h. The reaction was quenched by the addition of water (500 mL). The resulting mixture was extracted with DCM (2×300 mL). The organic layers were combined, washed with sodium bicarbonate solution (sat., 300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:10 to 1:5 ethyl acetate/pet. ether). The collected fraction was concentrated under vacuum to afford trans-ethyl 1-benzyl-4-(difluoromethyl)pyrrolidine-3-carboxylate as a yellow oil. MS (ESI, m/z): 284 [M+H]⁺.

Step 4. trans-Ethyl 4-(difluoromethyl)pyrrolidine-3-carboxylate

A mixture of trans-ethyl-1-benzyl-4-(difluoromethyl)pyrrolidine-3-carboxylate (5.50 g, 19.4 mmol) and Pd(OH)₂/C (2.00 g, 10%) in MeOH (30 mL) was stirred for 2 h at 25° C. under hydrogen atmosphere (balloon). The solids were filtered out and the filter cake was washed with MeOH (3×10 mL). The filtrate was concentrated under reduced pressure to afford trans-ethyl 4-(difluoromethyl)pyrrolidine-3-carboxylate as a white solid. MS (ESI, m/z): 194 [M+H]⁺.

Step 5. trans-Benzyl 3-(difluoromethyl)-4-[ethoxy(hydroxy)methyl]pyrrolidine-1-carboxylate

CbzCl (4.05 g, 23.741 mmol) was added into a stirring solution of trans-ethyl 4-(difluoromethyl)pyrrolidine-3-carboxylate (3.90 g, 19.8 mmol) and K₂CO₃ (8.20 g, 59.3 mmol) in H₂O (20 mL) and ethyl acetate (40 mL) at 0° C. The resulting mixture was stirred for 1 h at 25° C. The reaction was quenched by the addition of water (100 mL). The resulting mixture was extracted with DCM (2×200 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by reverse phase chromatography (column, C₁₈ silica gel; Mobile phase, A: water (containing 0.1% TFA) and B: ACN (0% to 60% in 30 min)) to afford trans-benzyl 3-(difluoromethyl)-4-[ethoxy(hydroxy)methyl]pyrrolidine-1-carboxylate as a yellow oil. MS (ESI, m/z): 328 [M+H]⁺.

Step 6. trans-1-[(Benzyloxy)carbonyl]-4-(difluoromethyl)pyrrolidine-3-carboxylic Acid

To a stirring solution of trans-benzyl 3-(difluoromethyl)-4-[ethoxy(hydroxy)methyl]pyrrolidine-1-carboxylate (6.00 g, 18.0 mmol) in THF (80 mL) and MeOH (20 mL) was added a solution of LiOH (4.30 g, 180 mmol) in water (10 mL). The resulting mixture was stirred for 1 h at 25° C. The solvent was removed under vacuum. pH value of the residue was adjusted to 5-6 with NH₄C₁ (sat. aq.). The resulting mixture was extracted with DCM (3×50 mL). The organic layers were combined, washed with sodium bicarbonate solution (sat., 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by reverse phase chromatography (column: C₁₈ silica gel; Mobile phase, A: water (containing 0.1% TFA) and B: ACN (0% to 60% in 30 min)) to afford trans-1-[(benzyloxy)carbonyl]-4-(difluoromethyl)pyrrolidine-3-carboxylic acid as a colorless oil. MS (ESI, m/z): 300 [M+H]⁺.

Step 7. trans-Benzyl 3-[[(tert-butoxy)carbonyl]amino]-4-(difluoromethyl)pyrrolidine-1-carboxylate

To a stirring solution of trans-1-[(benzyloxy)carbonyl]-4-(difluoromethyl)pyrrolidine-3-carboxylic acid (4.00 g, 13.1 mmol) in t-BuOH (100 mL) were added Et₃N (2.73 mL, 19.6 mmol) and DPPA (4.33 g, 15.7 mmol) dropwise at 0° C. After addition, the resulting mixture was stirred for 2 h at 80° C. The mixture was allowed to cool down to 25° C. and then concentrated under vacuum. The residue was purified by reverse flash chromatography (column, C₁₈ silica gel; Mobile phase, A: water (containing 0.1% TFA) and B: ACN (0% to 100% in 40 min)) to afford desired product. It was further purified by silica gel chromatography (eluting with 2:5 THF/pet. ether) to afford trans-benzyl 3-[[(tert-butoxy)carbonyl]amino]-4-(difluoromethyl)pyrrolidine-1-carboxylate as a colorless oil. MS (ESI, m/z): 371 [M+H]⁺.

Step 8. Tert-Butyl N-[(3S,4R)-4-(difluoromethyl)pyrrolidin-3-yl]carbamate and tert-butyl N-[(3R,4S)-4-(difluoromethyl)pyrrolidin-3-yl]carbamate

trans-Benzyl 3-[[(tert-butoxy)carbonyl]amino]-4-(difluoromethyl)pyrrolidine-1-carboxylate (1.70 g, 4.58 mmol) was separated by SFC (Column: Chiralpak AD-H SFC, 5×25 cm, 5 μm; Mobile Phase, A: CO₂:70% and B: MeOH (containing 2 mM NH₃—MeOH): 30%; Flow rate: 180 mL/min) to afford the first eluted isomer (RT=4.23 min) as a white solid, the stereochemistry arbitrarily assigned as tert-butyl N-[(3R,4S)-4-(difluoromethyl)pyrrolidin-3-yl]carbamate; and the second eluted isomer (RT=6.14 min) as a white solid, the stereochemistry arbitrarily assigned as tert-butyl N-[(3S,4R)-4-(difluoromethyl)pyrrolidin-3-yl]carbamate. MS (ESI, m/z): 371 [M+H]⁺.

Step 9. Tert-Butyl N-[(3S,4R)-4-(difluoromethyl)pyrrolidin-3-yl]carbamate and tert-Butyl N-[(3R,4S)-4-(difluoromethyl)pyrrolidin-3-yl]carbamate

A mixture of benzyl (3S,4R)-3-[[(tert-butoxy)carbonyl]amino]-4-(difluoromethyl)pyrrolidine-1-carboxylate (650 mg, 1.76 mmol) and Pd/C (450 mg, 10%) in ethyl acetate (14 mL) was stirred for 3 h at 25° C. under an atmosphere of hydrogen (balloon). The solids were filtered out. The filtrate was concentrated under vacuum to give tert-butyl N-[(3S,4R)-4-(difluoromethyl)pyrrolidin-3-yl]carbamate as a colorless oil. MS (ESI, m/z): 237 [M+H]⁺.

Tert-Butyl N-[(3R,4S)-4-(difluoromethyl)pyrrolidin-3-yl]carbamate was similarly obtained from benzyl (3R,4S)-3-[[(tert-butoxy)carbonyl]amino]-4-(difluoromethyl)pyrrolidine-1-carboxylate. MS (ESI, m/z): 237 [M+H]⁺.

Step 1. Benzyl N-benzyl-N-[(6S)-2-(trifluoromethanesulfonyloxy)-5,6,7,8-tetrahydroquinolin-6-yl]carbamate

NaH (260 mg, 6.50 mmol, 60%) was added into a stirring solution of benzyl N-[(6S)-2-(trifluoromethanesulfonyloxy)-5,6,7,8-tetrahydroquinolin-6-yl]carbamate (Intermediate 47-2) (1.00 g, 2.23 mmol) in DMF (5 mL) in portions at 0° C. The resulting mixture was stirred for 30 min at 0° C. To the above mixture was added benzyl bromide (795 mg, 4.56 mmol) dropwise over 30 min at 0° C. The resulting mixture was stirred at 26° C. for 1 h. The reaction was quenched by the addition of water (30 mL) at 0° C. The resulting mixture was extracted with ethyl acetate (3×30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by reversed phase chromatography (Column: C₁₈ silica gel; Mobile phase, A: water (containing 10 mmol/L NH₄HCO₃) and B: ACN (5% to 80% in 30 min)). The collected fraction was concentrated to give benzyl N-benzyl-N-[(6S)-2-(trifluoromethanesulfonyloxy)-5,6,7,8-tetrahydroquinolin-6-yl]carbamate as a brown solid. MS (ESI, m/z): 521 [M+H]⁺.

Step 2. Benzyl N-benzyl-N-[(6S)-2-chloro-5,6,7,8-tetrahydroquinolin-6-yl]carbamate

A solution of benzyl N-benzyl-N-[(6S)-2-(trifluoromethanesulfonyloxy)-5,6,7,8-tetrahydroquinolin-6-yl]carbamate (925 mg, 1.69 mmol) and a solution of HCl (1 mL, 4M in dioxane) in dioxane (3 mL) was stirred for 15 min at 100° C. The mixture was allowed to cool to 25° C. and concentrated under vacuum. The residue was purified by reverse phase chromatography (Column: C₁₈ silica gel; Mobile phase, A: water (containing 10 mmol/L NH₄HCO₃) and B: ACN (5% to 80% in 30 min)). The collected fraction was concentrated to give benzyl N-benzyl-N-[(6S)-2-chloro-5,6,7,8-tetrahydroquinolin-6-yl]carbamate as a brown oil. MS (ESI, m/z): 407, 409 [M+H]⁺.

Step 3. (6S)-6-[Benzyl[(benzyloxy)carbonyl]amino]-2-chloro-5,6,7,8-tetrahydroquinolin-1-ium-1-olate

A solution of benzyl N-benzyl-N-[(6S)-2-chloro-5,6,7,8-tetrahydroquinolin-6-yl]carbamate (632 mg, 1.49 mmol) and m-CPBA (1.31 g, 7.46 mmol) in DCM (20 mL) was stirred for 16 h at 25° C. The reaction was quenched by the addition of Na₂SO₃ (sat. aq., 30 mL) and NaHCO₃ (sat. aq., 30 mL). The resulting mixture was extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:3 ethyl acetate/pet. ether) to afford (6S)-6-[benzyl[(benzyloxy)carbonyl]amino]-2-chloro-5,6,7,8-tetrahydroquinolin-1-ium-1-olate as a white solid. MS (ESI, m/z): 423, 425 [M+H]⁺.

Step 4. (6S)-6-[Benzyl[(benzyloxy)carbonyl]amino]-2-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-5,6,7,8-tetrahydroquinolin-1-ium-1-olate

A solution of (6S)-6-[benzyl[(benzyloxy)carbonyl]amino]-2-chloro-5,6,7,8-tetrahydroquinolin-1-ium-1-olate (470 mg, 1.06 mmol), tert-butyl piperazine-1-carboxylate (1.04 g, 5.58 mmol) and DIEA (0.990 mL, 5.57 mmol) in t-BuOH (5 mL) was stirred for 10 h at 90° C. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase chromatography (C₁₈ silica gel; Mobile phase, A: water (containing 10 mmol/L NH₄HCO₃) and B: ACN (5% to 80% in 30 min)). The collected fraction was concentrated to give (6S)-6-[benzyl[(benzyloxy)carbonyl]amino]-2-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-5,6,7,8-tetrahydroquinolin-1-ium-1-olate as a yellow solid. MS (ESI, m/z): 573 [M+H]⁺.

Step 5. TFA salt of (6S)-6-[benzyl[(benzyloxy)carbonyl]amino]-2-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-N,N,N-trimethyl-5,6,7,8-tetrahydroquinolin-4-aminium

A solution of (6S)-6-[benzyl[(benzyloxy)carbonyl]amino]-2-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-5,6,7,8-tetrahydroquinolin-1-ium-1-olate (460 mg, 0.760 mmol) in DCM (9 mL) was treated with a solution of trimethylamine (3.63 mL, 1M in THF) at 0° C., followed by the addition of Tf₂O (0.365 mL, 2.13 mmol) dropwise at 0° C. The resulting mixture was stirred for 1 h at 25° C. and then concentrated under vacuum. The residue was purified by reverse phase chromatography (Column: C₁₈ silica gel; Mobile phase, A: water (containing 10 mmol/L NH₄HCO₃) and B: ACN (5% to 80% in 30 min)). The collected fraction was concentrated to afford the TFA salt of (6S)-6-[benzyl[(benzyloxy)carbonyl]amino]-2-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-N,N,N-trimethyl-5,6,7,8-tetrahydroquinolin-4-aminium as a light brown solid. MS (ESI, m/z): 615 [M+H]⁺.

Step 6. Tert-Butyl 4-[(6S)-6-[benzyl[(benzyloxy)carbonyl]amino]-4-fluoro-5,6,7,8-tetrahydroquinolin-2-yl]piperazine-1-carboxylate

A solution of the TFA salt of (6S)-6-[benzyl[(benzyloxy)carbonyl]amino]-2-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-N,N,N-trimethyl-5,6,7,8-tetrahydroquinolin-4-aminium (230 mg, 0.300 mmol) and a solution of TBAF (3.30 mL, 1M in THF) in DMF (5 mL) was stirred for 2 h at 90° C. The mixture was purified by reverse phase chromatography (Column: C₁₈ silica gel; Mobile phase, A: water (containing 10 mmol/L NH₄HCO₃) and B: ACN (5% to 80% in 30 min)). The collected fraction was concentrated to give tert-butyl 4-[(6S)-6-[benzyl[(benzyloxy)carbonyl]amino]-4-fluoro-5,6,7,8-tetrahydroquinolin-2-yl]piperazine-1-carboxylate as a white solid. MS (ESI, m/z): 575 [M+H]⁺.

Step 7. Tert-Butyl 4-[(6S)-6-amino-4-fluoro-5,6,7,8-tetrahydroquinolin-2-yl]piperazine-1-carboxylate

A mixture of tert-butyl 4-[(6S)-6-[benzyl[(benzyloxy)carbonyl]amino]-4-fluoro-5,6,7,8-tetrahydroquinolin-2-yl]piperazine-1-carboxylate (100 mg, 0.170 mmol) and palladium on carbon (100 mg, 10%) in ethyl acetate (5 mL) was stirred for 3 h at 25° C. under hydrogen atmosphere. The solids were filtered out and the filter cake was washed with ethyl acetate (3×10 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl 4-[(65)-6-amino-4-fluoro-5,6,7,8-tetrahydroquinolin-2-yl]piperazine-1-carboxylate as a light brown solid. MS (ESI, m/z): 351 [M+H]⁺.

The following intermediate in Table 8 was prepared using standard chemical manipulations and procedures similar to those used for the preparation of Intermediate 52-1.

TABLE 8 Interme- LRMS diate Structure and Compound m/z Number Name [M + H]⁺ 52-2

  tert-butyl 3-[(6S)-6-amino-4- fluoro-5,6,7,8- tetrahydroquinolin-2-yl+-3,8- diazabicyclo[3.2.1]octane-8- carboxylate 377

Step 1. Ethyl (2E)-4-methoxybut-2-enoate

A mixture of ethyl (2E)-4-bromobut-2-enoate (33.0 g, 171 mmol), Ag₂O (39.6 g, 171 mmol) and MeOH (100 mL) was stirred for 12 h at 25° C. without light. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was purified via reverse phase chromatography (Column: C₁₈ silica gel; Mobile phase, A: water (containing 0.05% TFA) and B: ACN (5% to 75% in 20 min)). The collected fraction was concentrated under vacuum to give ethyl (2E)-4-methoxybut-2-enoate as yellow oil. MS (ESI, m/z): 145 [M+H]⁺.

Step 2. trans-Ethyl 1-benzyl-4-(methoxymethyl)pyrrolidine-3-carboxylate

A solution of TFA (0.480 mL, 4.20 mmol) in DCM (2 mL) was added to a stirring solution of ethyl (2E)-4-methoxybut-2-enoate (9.30 g, 64.5 mmol) and benzyl(methoxymethyl)[(trimethylsilyl)methyl]amine (22.9 g, 96.7 mmol) in DCM (400 mL) at <10° C. The resulting mixture was stirred for 2 h at 25° C. The reaction was quenched by the addition of NH₄HCO₃ (sat. aq., 150 mL). The resulting mixture was extracted with DCM (3×100 mL). The organic layers were combined, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 1:5 ethyl acetate/pet. ether) to afford trans-ethyl 1-benzyl-4-(methoxymethyl)pyrrolidine-3-carboxylate as a yellow oil. MS (ESI, m/z): 278 [M+H]⁺.

Step 3. trans-Ethyl 4-(methoxymethyl)pyrrolidine-3-carboxylate

A mixture of trans-ethyl 1-benzyl-4-(methoxymethyl)pyrrolidine-3-carboxylate (14.0 g, 50.4 mmol), Pd(OH)₂/C (8.43 g, 10%) and MeOH (200 mL) was stirred for 1 h at 25° C. under hydrogen atmosphere (balloon). The solids were filtered out. The filtrate was concentrated under vacuum to give trans-ethyl 4-(methoxymethyl)pyrrolidine-3-carboxylate as a yellow oil. MS (ESI, m/z): 188 [M+H]⁺.

Step 4. trans-1-Benzyl 3-ethyl 4-(methoxymethyl)pyrrolidine-1,3-dicarboxylate

CbzCl (9.01 mL, 64.0 mmol) was added into a mixture of trans-ethyl 4-(methoxymethyl)pyrrolidine-3-carboxylate (8.00 g, 42.7 mmol) and K₂CO₃ (14.7 g, 106 mmol) in ethyl acetate (100 mL) and H₂O (100 mL) at 0° C. The mixture was stirred for 1 h at 25° C. The mixture was extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:3 ethyl acetate/pet. ether) to afford trans-1-benzyl 3-ethyl 4-(methoxymethyl)pyrrolidine-1,3-dicarboxylate as a yellow oil. MS (ESI, m/z): 322 [M+H]⁺.

Step 5. trans-1-[(Benzyloxy)carbonyl]-4-(methoxymethyl)pyrrolidine-3-carboxylic Acid

A solution of trans-1-benzyl 3-ethyl 4-(methoxymethyl)pyrrolidine-1,3-dicarboxylate (5.00 g, 15.6 mmol) and NaOH (3.11 g, 77.7 mmol) in H₂O (40 mL), THF (40 mL) and MeOH (40 mL) was stirred for 2 h at 25° C. The solvent was removed under vacuum. The pH value of the residue was adjusted to pH 6 with hydrochloric acid (3N). The resulting mixture was extracted with ethyl acetate (3×25 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give trans-1-[(benzyloxy)carbonyl]-4-(methoxymethyl)pyrrolidine-3-carboxylic acid as yellow oil. MS (ESI, m/z): 294 [M+H]⁺.

Step 6. trans-Benzyl 3-[[(tert-butoxy)carbonyl]amino]-4-(methoxymethyl)pyrrolidine-1-carboxylate

A solution of trans-1-[(benzyloxy)carbonyl]-4-(methoxymethyl)pyrrolidine-3-carboxylic acid (3.00 g, 10.2 mmol), DPPA (3.38 g, 12.3 mmol), and Et₃N (4.25 mL, 30.6 mmol) in t-BuOH (60 mL) was stirred for 3 h at 80° C. The mixture was cooled to 25° C. and concentrated under vacuum. The residue was purified via reverse phase chromatography (Column: C₁₈ silica gel; Mobile phase, A: water (containing 0.05% TFA) and B: ACN (5% to 75% in 20 min)). The collected fraction was concentrated under vacuum to give a crude product. The crude product was purified by silica gel chromatography (eluting with 1:3 THF/pet. ether) to afford trans-benzyl 3-[[(tert-butoxy)carbonyl]amino]-4-(methoxymethyl)pyrrolidine-1-carboxylate as a colorless oil. MS (ESI, m/z): 365 [M+H]⁺.

Step 7. trans-tert-Butyl N-[1-benzyl-4-(methoxymethyl)pyrrolidin-3-yl]-N-methylcarbamate

NaH (59.0 mg, 1.48 mmol, 60%) was added to a solution of trans-tert-butyl N-[1-benzyl-4-(methoxymethyl)pyrrolidin-3-yl]carbamate (350 mg, 0.983 mmol) in DMF (4 mL) at 0° C. The resulting solution was stirred for 30 min at 0° C. Then CH₃I (0.018 mL, 0.281 mmol) was added at 0° C. The resulting mixture was stirred for additional 2 h at 25° C. The reaction was quenched with water (50 mL). The resulting mixture was extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 1:3 ethyl acetate/pet. ether) to afford trans-tert-butyl N-[1-benzyl-4-(methoxymethyl)pyrrolidin-3-yl]-N-methylcarbamate as a white solid. MS (ESI, m/z): 379 [M+H]⁺.

Step 8. trans-tert-Butyl N-[4-(methoxymethyl)pyrrolidin-3-yl]-N-methylcarbamate

A mixture of trans-tert-butyl N-[1-benzyl-4-(methoxymethyl)pyrrolidin-3-yl]-N-methylcarbamate (330 mg, 0.828 mmol) and palladium on carbon (300 mg, 10%) in ethyl acetate (10 mL) was stirred for 3 h at 25° C. under hydrogen atmosphere (balloon). The resulting mixture was filtered. The filtrate was concentrated under reduced pressure to afford trans-tert-butyl N-[4-(methoxymethyl)pyrrolidin-3-yl]-N-methylcarbamate as a colorless oil. MS (ESI, m/z): 245 [M+H]⁺.

Step 1. 1-Benzyl-4-(hydroxymethyl)pyrrolidin-2-one

NaBH₄ (24.0 g, 634 mmol) was added to a solution of methyl 1-benzyl-5-oxopyrrolidine-3-carboxylate (50.0 g, 214 mmol) in ethanol (800 mL) at 0° C. The resulting solution was stirred for 4 h at 25° C. The reaction was quenched with water (50 mL). The mixture was concentrated under vacuum. The residue was diluted with water (200 mL). The resulting mixture was extracted with DCM (3×500 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 10:1 dicholoromethane/methanol) to give 1-benzyl-4-(hydroxymethyl)pyrrolidin-2-one as colorless oil. MS (ESI, m/z): 206 [M+H]⁺.

Step 2. 1-Benzyl-4-(fluoromethyl)pyrrolidin-2-one

DAST (32.2 mL, 244 mmol) was added to a solution of 1-benzyl-4-(hydroxymethyl)pyrrolidin-2-one (20.0 g, 97.5 mmol) in DCM (300 mL) at −78° C. The resulting solution was stirred for 16 h at 25° C. The reaction was poured into ice-water (200 mL). The resulting mixture was extracted with DCM (3×200 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified via reverse phase chromatography (Column: C₁₈ column; Mobile phase, A: water (containing 10 mmol/L NH₄HCO₃) and B: ACN (0% to 50% in 45 min)) to give 1-benzyl-4-(fluoromethyl)pyrrolidin-2-one as yellow oil. MS (ESI, m/z): 208 [M+H]⁺.

Step 3. trans-1-Benzyl-4-(fluoromethyl)-3-hydroxypyrrolidin-2-one

A solution of LDA (24.0 mL, 2M in THF) was added to a solution of 1-benzyl-4-(fluoromethyl)pyrrolidin-2-one (5.00 g, 23.6 mmol) in THF (100 mL) at −78° C. The resulting solution was stirred for 1 h at −78° C. Then 02 was introduced in. The resulting solution was stirred for 3 h at −78° C. The reaction was quenched by the addition of water (50 mL). The solvent was removed under vacuum. The residue was extracted with DCM (3×100 mL). The organic layers were combined, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (Column: C₁₈ silica gel; Mobile phase, A: water (containing 0.1% TFA) and B: ACN (0% to 60% in 30 min)) to afford trans-1-benzyl-4-(fluoromethyl)-3-hydroxypyrrolidin-2-one as a brown oil. MS (ESI, m/z): 224 [M+H]⁺.

Step 4. trans-1-Benzyl-4-(fluoromethyl)-2-oxopyrrolidin-3-yl methanesulfonate

MSCl (2.75 mL, 35.5 mmol) was added to a stirring solution of trans-1-benzyl-4-(fluoromethyl)-3-hydroxypyrrolidin-2-one (5.40 g, 23.7 mmol) and Et₃N (6.59 mL, 47.4 mmol) in DCM (70 mL) at 0° C. The resulting mixture was stirred for 2 h at 25° C. The reaction was quenched by the addition of water (50 mL) at 0° C. The resulting mixture was extracted with DCM (3×50 mL). The organic layers were combined, dried over anhydrous Na₂SO₄, filtered concentrated under reduced pressure to afford trans-1-benzyl-4-(fluoromethyl)-2-oxopyrrolidin-3-yl methanesulfonate as a brown oil. MS (ESI, m/z): 302 [M+H]⁺.

Step 5. Cis-3-Azido-1-benzyl-4-(fluoromethyl)pyrrolidin-2-one

A mixture of trans-1-benzyl-4-(fluoromethyl)-2-oxopyrrolidin-3-yl methanesulfonate (6.00 g, 19.5 mmol) and NaN₃ (3.81 g, 58.6 mmol) in DMF (150 mL) was stirred for 1 h at 100° C. The mixture was allowed to cool down to 25° C. The reaction was quenched by the addition of water (500 mL) at 25° C. The resulting mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 1:1 ethyl acetate/pet. ether) to afford cis-3-azido-1-benzyl-4-(fluoromethyl)pyrrolidin-2-one as a yellow oil. MS (ESI, m/z): 249 [M+H]⁺.

Step 6. Cis-tert-Butyl N-[1-benzyl-4-(fluoromethyl)-2-oxopyrrolidin-3-yl]carbamate

A mixture of 3-azido-1-benzyl-4-(fluoromethyl)pyrrolidin-2-one (4.00 g, 15.8 mmol), Palladium on carbon (4.00 g, 10%) and di-tert-butyl dicarbonate (6.89 g, 31.6 mmol) in EtOH (100 mL) was stirred for 3 h at 25° C. under hydrogen atmosphere (balloon). The solids were filtered out. The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:1 ethyl acetate/pet. ether) to afford cis-tert-butyl N-[1-benzyl-4-(fluoromethyl)-2-oxopyrrolidin-3-yl]carbamate as a white solid. MS (ESI, m/z): 323 [M+H]⁺.

Step 7. Cis-tert-Butyl N-[1-benzyl-4-(fluoromethyl)pyrrolidin-3-yl]carbamate

A solution of BH₃ (30 mL, 1M in THF) was added to a stirring solution of cis-tert-butyl N-[1-benzyl-4-(fluoromethyl)-2-oxopyrrolidin-3-yl]carbamate (2.40 g, 7.30 mmol) in THF (60 mL) at 0° C. The resulting mixture was stirred for 16 h at 25° C. The resulting mixture was concentrated under vacuum. Then EtOH (60 mL), H₂O (15 mL) and Et₃N (15 mL) were added. The resulting mixture was stirred for 2 h at 80° C. The resulting mixture was cooled to 25° C. and concentrated under vacuum. The residue was purified by reverse phase chromatography (Column: C18 Column; Mobile phase, A: water (containing 10 mmol/L NH₄HCO₃) and B: ACN (0% to 100% in 30 min)) to afford cis-tert-butyl N-[1-benzyl-4-(fluoromethyl)pyrrolidin-3-yl]carbamate as a white solid. MS (ESI, m/z): 309 [M+H]⁺.

Step 8. Cis-tert-Butyl N-[4-(fluoromethyl)pyrrolidin-3-yl]carbamate

A mixture of tert-butyl N-[1-benzyl-4-(fluoromethyl)pyrrolidin-3-yl]carbamate (450 mg, 1.43 mmol) and Pd(OH)₂/C (450 mg, 10%) in ethyl acetate (10 mL) was stirred for 2 h at 25° C. under hydrogen atmosphere (balloon). The resulting mixture filtered. The filtrate was concentrated under reduced pressure to afford cis-tert-butyl N-[4-(fluoromethyl)pyrrolidin-3-yl]carbamate as a brown oil. MS (ESI, m/z): 219 [M+H]⁺.

Step 1. trans-Benzyl 3-azido-4-(2-methoxyethoxy)pyrrolidine-1-carboxylate

NaH (1.91 g, 47.7 mmol, 60%) was added into a stirring solution of trans-benzyl 3-azido-4-hydroxypyrrolidine-1-carboxylate (5.00 g, 19.1 mmol) in DMF (70 mL) at <10° C. The resulting solution was stirred for 30 min at <10° C. Then 1-bromo-2-methoxyethane (7.95 g, 57.2 mmol) was added to the mixture at <10° C. The resulting mixture was stirred for 3 h at 26° C. The reaction was then quenched by the addition of water/ice (70 mL). The resulting mixture was extracted with ethyl acetate (3×100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under vacuum. The residue was purified via reverse phase chromatography (Column: C₁₈ silica gel; Mobile phase, A: water (containing 0.05% TFA) and B: ACN (10% to 75% in 25 min)). The collected fraction was concentrated under vacuum to give trans-benzyl 3-azido-4-(2-methoxyethoxy)pyrrolidine-1-carboxylate as yellow oil. MS (ESI, m/z): 321 [M+H]⁺.

Step 2. trans-Benzyl 3-amino-4-(2-methoxyethoxy)pyrrolidine-1-carboxylate

A mixture of trans-benzyl 3-azido-4-(2-methoxyethoxy)pyrrolidine-1-carboxylate (5.60 g, 17.4 mmol) and PtO₂ (2.00 g, 8.80 mmol) in ethyl acetate (100 mL) was stirred for 1 h at 26° C. under hydrogen atmosphere (balloon). The solids were filtered out. The filtrate was concentrated under vacuum to give trans-benzyl 3-amino-4-(2-methoxyethoxy)pyrrolidine-1-carboxylate as a black oil. MS (ESI, m/z): 295 [M+H]⁺.

Step 3. trans-Benzyl 3-[[(tert-butoxy)carbonyl]amino]-4-(2-methoxyethoxy)pyrrolidine-1-carboxylate

(Boc)₂O (5.45 g, 25.0 mmol) was added into a solution of trans-benzyl 3-amino-4-(2-methoxyethoxy)pyrrolidine-1-carboxylate (5.00 g, 17.0 mmol) and Et₃N (7.08 mL, 70.0 mmol) in THF (70 mL) and H₂O (70 mL). The resulting solution was stirred for 3 h at 26° C. THF was removed under vacuum. The residue was extracted with ethyl acetate (3×100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:3 ethyl acetate/pet. ether) to afford trans-benzyl 3-[[(tert-butoxy)carbonyl]amino]-4-(2-methoxyethoxy)pyrrolidine-1-carboxylate as yellow oil. MS (ESI, m/z): 395 [M+H]⁺.

Step 4. trans-tert-Butyl N-[4-(2-methoxyethoxy)pyrrolidin-3-yl]carbamate

A mixture of trans-benzyl 3-[[(tert-butoxy)carbonyl]amino]-4-(2-methoxyethoxy)pyrrolidine-1-carboxylate (1.60 g, 4.06 mmol) and palladium on carbon (1.60 g, 10%) in ethyl acetate (30 mL) was stirred for 2 h at 26° C. under hydrogen atmosphere (balloon). The solids were filtered out. The filtrate was concentrated under vacuum to give trans-tert-butyl N-[4-(2-methoxyethoxy)pyrrolidin-3-yl]carbamate as light yellow oil. MS (ESI, m/z): 261 [M+H]⁺.

Step 1. Benzyl (3S,4S)-3-azido-4-(propan-2-yloxy)pyrrolidine-1-carboxylate

Sodium hydride (688 mg, 17.2 mmol, 60%) was added to a stirring solution of benzyl (3S,4S)-3-azido-4-hydroxypyrrolidine-1-carboxylate (3.00 g, 11.44 mmol), 2-bromopropane (10.7 mL, 113 mmol) and KI (3.80 g, 2.89 mmol), in DMF (100 mL) at 0° C. The resulting solution was stirred for 3 h at 50° C. After cooling to 25° C., the reaction was quenched by the addition of H₂O/ice (100 mL). The resulting mixture was extracted with ethyl acetate (3×200 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and then concentrated under vacuum. The residue was purified by reversed phase chromatography (Column, C₁₈ silica gel; Mobile phase, A: water (containing 0.05% formic acid) and B: ACN (0% to 80% within 40 min)). The collected fraction was concentrated under vacuum to give benzyl (3S,4S)-3-azido-4-(propan-2-yloxy)pyrrolidine-1-carboxylate as colorless oil. MS (ESI, m/z): 305 [M+H]⁺.

Step 2. Benzyl (3S,4S)-3-amino-4-(propan-2-yloxy)pyrrolidine-1-carboxylate

A mixture of benzyl (3S,4S)-3-azido-4-(propan-2-yloxy)pyrrolidine-1-carboxylate (220 mg, 0.72 mmol) and PtO₂ (33.0 mg, 0.150 mmol) in ethyl acetate (10 mL) was stirred for 2 h at 25° C. under hydrogen atmosphere (balloon). The solids were filtered out. The filtrate was concentrated under vacuum to give benzyl (3S,4S)-3-amino-4-(propan-2-yloxy)pyrrolidine-1-carboxylate as brown oil. MS (ESI, m/z): 279 [M+H]⁺.

Step 3. Benzyl (3S,4S)-3-[[(tert-butoxy)carbonyl]amino]-4-(propan-2-yloxy)pyrrolidine-1-carboxylate

A solution of benzyl (3S,4S)-3-amino-4-(propan-2-yloxy)pyrrolidine-1-carboxylate (200 mg, 0.720 mmol), Et₃N (0.190 mL, 1.35 mmol) and (Boc)₂O (236 mg, 1.08 mmol) in THF (5 mL) and water (5 mL) was stirred for 30 min at 25° C. The solvent was removed under vacuum. The residue was diluted with water (10 mL). The resulting mixture was extracted with ethyl acetate (3×20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by a silica gel chromatography (eluting with 1:5 ethyl acetate/pet. ether) to give benzyl (3S,4S)-3-[[(tert-butoxy)carbonyl]amino]-4-(propan-2-yloxy)pyrrolidine-1-carboxylate as colorless oil. MS (ESI, m/z): 379 [M+H]⁺.

Step 4. Tert-Butyl N-[(3S,4S)-4-(propan-2-yloxy)pyrrolidin-3-yl]carbamate

A mixture of benzyl (3S,4S)-3-[[(tert-butoxy)carbonyl]amino]-4-(propan-2-yloxy)pyrrolidine-1-carboxylate (250 mg, 0.660 mmol) and Palladium on carbon (250 mg, 10%) in ethyl acetate (5 mL) was stirred for 2 h at 25° C. under hydrogen atmosphere (balloon). The solids were filtered out. The filtered was concentrated under vacuum to give tert-butyl N-[(3S,4S)-4-(propan-2-yloxy)pyrrolidin-3-yl]carbamate as a brown solid. MS (ESI, m/z): 245 [M+H]⁺.

Step 1. Benzyl N-[(3Z)-3-[(dimethylamino)methylidene]-4-oxocyclohexyl]carbamate

A solution of benzyl N-(4-oxocyclohexyl)carbamate (10.0 g, 40.4 mmol) and (dimethoxymethyl)dimethylamine (4.80 g, 40.4 mmol) in toluene (20 mL) was stirred for 16 h at 100° C. The resulting mixture was concentrated under vacuum to give benzyl N-[(3Z)-3-[(dimethylamino)methylidene]-4-oxocyclohexyl]carbamate as yellow oil. MS (ESI, m/z): 303 [M+H]⁺.

Step 2. Benzyl N-(2-amino-5,6,7,8-tetrahydroquinazolin-6-yl)carbamate

A solution of guanidine hydrochloride (3.45 g, 36.1 mmol) and sodiumethoxide (2.47 g, 36.3 mmol) in ethanol (150 mL) was stirred for 30 min at 23° C. Benzyl N-[(3Z)-3-[(dimethylamino)methylidene]-4-oxocyclohexyl]carbamate (11 g, 21.8 mmol, purity: 60%) was then added. The resulting solution was stirred for overnight at 80° C. The resulting mixture was concentrated under vacuum. The residue was purified by a silica gel chromatography (eluting with 1:10 MeOH/DCM) to give benzyl N-(2-amino-5,6,7,8-tetrahydroquinazolin-6-yl)carbamate as a white solid. S (ESI, m/z): 299 [M+H]⁺.

Step 3. Benzyl N-(2-chloro-5,6,7,8-tetrahydroquinazolin-6-yl)carbamate

A mixture of benzyl N-(2-amino-5,6,7,8-tetrahydroquinazolin-6-yl)carbamate (1.85 g, 6.20 mmol), t-BuNO₂ (3.72 mL, 31.0 mmol) and CuCl₂ (4.14 g, 30.8 mmol) in ACN (40 mL) was stirred for 20 min at 60° C. The reaction mixture was cooled to 25° C. and diethyl ether (20 mL) was added. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was purified by reversed phase chromatography (Column: C₁₈ silica gel; Mobile phase, A: water (containing 0.05% NH₄HCO₃) and B: ACN (5% to 80% in 30 min)) to afford benzyl N-(2-chloro-5,6,7,8-tetrahydroquinazolin-6-yl)carbamate as a white solid. MS (ESI, m/z): 318, 320 [M+H]⁺.

Step 1. RuCl—(S,S)-Ts-DPEN(hexamethylbenzene)

A solution of N-[(1S,2S)-2-amino-1,2-diphenylethyl]-4-methylbenzene-1-sulfonamide (S,S-Ts-DPEN) (1.09 g, 3.00 mmol), Et₃N (0.90 mL, 6.47 mmol), and [RuCl₂(hexamethylbenzene)]2 (1.00 g, 1.50 mmol) in DCM (40 mL) was stirred for 5 h at 25° C. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:10 MeOH/DCM) to afford RuCl—(S,S)-Ts-DPEN(hexamethylbenzene) as a red solid.

Step 2. RuCl—(S,S)-Ts-DPEN-OTf(hexamethylbenzene)

A solution of RuCl—(S,S)-Ts-DPEN(hexamethylbenzene) (1.95 g, 2.99 mmol) and silver trifluoromethanesulfonate (0.800 g, 3.17 mmol) in DCM (50 mL) was stirred for 6 h at 25° C. The solids were filtered out. The filtrate was concentrated under vacuum to afford RuCl—(S,S)-Ts-DPEN-OTf(hexamethylbenzene) as a brown solid.

Step 3. Ethyl 6-chloro-4-methylpyridine-3-carboxylate

Sulfuric acid (15.6 mL, 306 mmol) was added into a solution of 6-chloro-4-methylpyridine-3-carboxylic acid (10.0 g, 58.3 mmol) in EtOH (250 mL). The resulting solution was stirred for 48 h at 25° C. A saturated solution of NaHCO₃ in water (500 mL) was added to the reaction. Then EtOH was evaporated out. The residue was extracted with DCM (2×500 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:15 ethyl acetate/pet. ether) to give ethyl 6-chloro-4-methylpyridine-3-carboxylate as a white solid. MS (ESI, m/z): 200, 202 [M+H]⁺.

Step 4. Methyl 3-chloro-8-hydroxy-5,6-dihydroisoquinoline-7-carboxylate

A solution of LDA (12.5 mL, 2M in THF) was added to a solution of ethyl 6-chloro-4-methylpyridine-3-carboxylate (2.00 g, 10.0 mmol) in THF (100 mL) at −78° C. The resulting solution was stirred for 1 h at −78° C. Then methyl prop-2-enoate (2.25 mL, 24.9 mmol) was added and the reaction was stirred for 1 h at −78° C. The reaction was then quenched with water (50 mL). THF was removed in vacuo. The aqueous layer was extracted with DCM (3×50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:10 ethyl acetate/pet. ether) to give methyl 3-chloro-8-hydroxy-5,6-dihydroisoquinoline-7-carboxylate as a white solid. MS (ESI, m/z): 240, 242 [M+H]⁺.

Step 5. Methyl 3-chloro-8-hydroxy-5,6,7,8-tetrahydroisoquinoline-7-carboxylate

Et₃N (7.62 mL, 54.8 mmol) was added to a solution of formic acid (1.89 mL, 50.1 mmol) in MeOH (90 mL) at 0° C. Then methyl 3-chloro-8-hydroxy-5,6-dihydroisoquinoline-7-carboxylate (3.00 g, 12.5 mmol) and RuCl—(S,S)-Ts-DPEN-OTf(hexamethylbenzene) (82 mg, 0.099 mmol) was added. The resulting solution was stirred for 16 h at 25° C. The reaction was then poured into water (200 mL). The solvent was removed in vacuo. The aqueous layer was extracted with DCM (3×150 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:5 ethyl acetate/pet. ether) to give methyl 3-chloro-8-hydroxy-5,6,7,8-tetrahydroisoquinoline-7-carboxylate as a white solid. MS (ESI, m/z): 242, 244 [M+H]⁺.

Step 6. Methyl 3-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-5,6-dihydroisoquinoline-7-carboxylate

A mixture of methyl 3-chloro-8-hydroxy-5,6,7,8-tetrahydroisoquinoline-7-carboxylate (0.500 g, 2.07 mmol), tert-butyl piperazine-1-carboxylate (0.750 g, 4.03 mmol), RuPhos Pd G3 (100 mg, 0.120 mmol), RuPhos (62.0 mg, 0.140 mmol) and Cs₂CO₃ (2.00 g, 6.16 mmol) in toluene (10 mL) was stirred for 16 h at 95° C. Four batches of this reaction was set up in parallel. After cooling to room temperature, the four batches of reaction mixture were poured into water (100 mL). The resulting mixture was extracted with acyl acetate (3×100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:4 ethyl acetate/pet. ether) to give methyl 3-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-5,6-dihydroisoquinoline-7-carboxylate as a white solid). MS (ESI, m/z): 374 [M+H]⁺.

Step 7. Methyl 3-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-5,6-dihydroisoquinoline-7-carboxylate

A mixture of methyl 3-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-5,6-dihydroisoquinoline-7-carboxylate (550 mg, 1.47 mmol) and Palladium on carbon (500 mg, 10%) in ethyl acetate (20 mL) was stirred for 3 h at 25° C. under hydrogen atmosphere (balloon). The solids were filtered out. The filtrate was concentrated under vacuum to give methyl 3-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-5,6,7,8-tetrahydroisoquinoline-7-carboxylate as a white solid. MS (ESI, m/z): 376 [M+H]⁺.

Step 8. 3-[4-[(tert-Butoxy)carbonyl]piperazin-1-yl]-5,6,7,8-tetrahydroisoquinoline-7-carboxylic acid

A solution of LiOH (200 mg, 8.35 mmol) in water (20 mL) was added to a solution of methyl 3-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-5,6,7,8-tetrahydroisoquinoline-7-carboxylate (500 mg, 1.33 mmol) in THF (20 mL). The resulting solution was stirred for 2 h at 25° C. The resulting solution was concentrated under vacuum. The residue was purified via reverse phase chromatography (Column: X Bridge C18, 19×150 mm, 5 um; Mobile phase, A: water (containing 0.05% TFA) and B: ACN (0% to 30% in 25 min)). The collected fraction was concentrated under vacuum to give 3-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-5,6,7,8-tetrahydroisoquinoline-7-carboxylic acid as a white solid. MS (ESI, m/z): 362 [M+H]⁺.

Step 9. Tert-Butyl 4-(7-[[(benzyloxy)carbonyl]amino]-5,6,7,8-tetrahydroisoquinolin-3-yl)piperazine-1-carboxylate

A solution of 3-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-5,6,7,8-tetrahydroisoquinoline-7-carboxylic acid (400 mg, 1.11 mmol), DPPA (476 mL, 2.20 mmol) and Et₃N (0.460 mL, 3.72 mmol) in toluene (6 mL) was stirred for 2 h at 25° C. and then 2 h at 70° C. Then benzyl alcohol (1.14 mL, 11.0 mmol) was added. The resulting solution was stirred for 2 h at 70° C. After cooling to room temperature, the reaction was then poured into water (30 mL). The resulting mixture was extracted with acyl acetate (3×20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:1 ethyl acetate/pet. ether) to give tert-butyl 4-(7-[[(benzyloxy)carbonyl]amino]-5,6,7,8-tetrahydroisoquinolin-3-yl)piperazine-1-carboxylate as colorless oil. MS (ESI, m/z): 467 [M+H]⁺.

Step 10. Tert-Butyl 4-(7-amino-5,6,7,8-tetrahydroisoquinolin-3-yl)piperazine-1-carboxylate

A mixture of tert-butyl 4-(7-[[(benzyloxy)carbonyl]amino]-5,6,7,8-tetrahydroisoquinolin-3-yl)piperazine-1-carboxylate (200 mg, 0.430 mmol) and K₃PO₄ (228 mg, 1.07 mmol) in DMA (5 mL) was stirred for 1 h at 90° C. After cooling to room temperature, the residue was purified via reverse phase chromatography (Column: X Bridge C18, 19×150 mm, 5 um; Mobile Phase, A: water (containing 10 mmol/L NH₄HCO₃) and B: ACN (10% to 50% in 30 min)). The collected fraction was concentrated under vacuum to give tert-butyl 4-(7-amino-5,6,7,8-tetrahydroisoquinolin-3-yl)piperazine-1-carboxylate as a white solid. MS (ESI, m/z): 333 [M+H]⁺.

Step 1. 7-Benzyl 9-(2-hydroxyethyl) 1,4-dioxa-7-azaspiro[4.4]nonane-7,9-dicarboxylate

A mixture of 1-benzyl 3-ethyl 4-oxopyrrolidine-1,3-dicarboxylate (5.00 g, 17.2 mmol), ethane-1,2-diol (3.20 g, 51.5 mmol), and PTSA (296 mg, 1.72 mmol) in toluene (100 mL) was stirred for 3 h at 110° C. with a Dean-Stark tube. The mixture was cooled to 27° C. and concentrated under vacuum. The residue was purified by reverse phase chromatography (Column: C₁₈ silica gel; Mobile phase, A: water (containing 0.05% TFA) and B: ACN (5% to 55% in 20 min)) to afford 7-benzyl 9-(2-hydroxyethyl) 1,4-dioxa-7-azaspiro[4.4]nonane-7,9-dicarboxylate as yellow oil. MS (ESI, m/z): 352 [M+H]⁺.

Step 2. 7-[(Benzyloxy)carbonyl]-1,4-dioxa-7-azaspiro[4.4]nonane-9-carboxylic acid

A mixture of 7-benzyl 9-(2-hydroxyethyl) 1,4-dioxa-7-azaspiro[4.4]nonane-7,9-dicarboxylate (2.80 g, 7.96 mmol) and sodium hydroxide (199 mg, 4.98 mmol) in MeOH (40 mL), THF (40 mL) and H₂O (40 mL) was stirred for 2 h at 28° C. THF and MeOH were removed under vacuum. The resulting mixture was acidified to pH 7-8 with HCl (1M), and then concentrated under vacuum. The residue was purified by reverse phase chromatography (Column: C₁₈ silica gel; Mobile phase, A: water (containing 0.05% TFA) and B: ACN (5% to 30% in 20 min)) to afford 7-[(benzyloxy)carbonyl]-1,4-dioxa-7-azaspiro[4.4]nonane-9-carboxylic acid as yellow oil. MS (ESI, m/z): 308 [M+H]⁺.

Step 3. Benzyl 9-[[(tert-butoxy)carbonyl]amino]-1,4-dioxa-7-azaspiro[4.4]nonane-7-carboxylate

DPPA (632 mg, 2.30 mmol) was added to a stirring solution of 7-[(benzyloxy)carbonyl]-1,4-dioxa-7-azaspiro[4.4]nonane-9-carboxylic acid (600 mg, 1.91 mmol) and Et₃N (0.398 mL, 2.87 mmol) in t-BuOH (10 mL) at 0° C. The resulting mixture was stirred for 2 h at 90° C. The mixture was allowed to cool. The resulting mixture was concentrated under vacuum. The mixture was purified by reverse phase chromatography (Column: C₁₈ silica gel; Mobile phase, A: H₂O (containing 10 mmol/L NH₄HCO₃) and B: ACN (0% to 60% over 30 min)) to afford benzyl 9-[[(tert-butoxy)carbonyl]amino]-1,4-dioxa-7-azaspiro[4.4]nonane-7-carboxylate as a yellow oil. MS (ESI, m/z): 379 [M+H]⁺.

Step 4. Tert-Butyl N-[1,4-dioxa-7-azaspiro[4.4]nonan-9-yl]carbamate

A mixture of benzyl 9-[[(tert-butoxy)carbonyl]amino]-1,4-dioxa-7-azaspiro[4.4]nonane-7-carboxylate (200 mg, 0.518 mmol) and Pd/C (200 mg, 10%) in EtOAc (5 mL) was stirred for 2 h at 25° C. under hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate (3×5 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl N-[1,4-dioxa-7-azaspiro[4.4]nonan-9-yl]carbamate as a brown. MS (ESI, m/z): 245 [M+H]⁺.

SYNTHETIC EXAMPLES OF COMPOUNDS OF FORMULA (I) Example 1-1. (R)-3-Amino-6-methyl-N-(7-(piperazin-1-yl)chroman-3-yl)thieno[2,3-b]pyridine-2-carboxamide and Example 1-2. (S)-3-Amino-6-methyl-N-(7-(piperazin-1-yl)chroman-3-yl)thieno[2,3-b]pyridine-2-carboxamide

Step 1. Tert-Butyl 4-(3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)chroman-7-yl)piperazine-1-carboxylate

A solution of tert-butyl 4-(3-aminochroman-7-yl)piperazine-1-carboxylate, Intermediate 12, (130 mg, 0.27 mmol), EDCI (81 mg, 0.42 mmol), HOBt (57 mg, 0.42 mmol), DIEA (108 mg, 0.84 mmol), 3-amino-6-methylthieno[2,3-b]pyridine-2-carboxylic acid (58 mg, 0.28 mmol) in DMF (5 mL) was stirred for 18 h at room temperature. The reaction was quenched with 20 mL of water and was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (30 mL×2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. Purification by prep-HPLC (Column:)(Bridge Prep C18 OBD, 19×50 mm, 5 μm; Mobile phase A: water (10 mM NH₄HCO₃), B: ACN; Gradient: 40% B to 60% B in 13 min) afforded tert-butyl 4-(3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)chroman-7-yl)piperazine-1-carboxylate.

Step 2. Tert-Butyl (R)-4-(3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)chroman-7-yl)piperazine-1-carboxylate and tert-Butyl (S)-4-(3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)chroman-7-yl)piperazine-1-carboxylate

The racemic mixture of tert-butyl 4-(3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)chroman-7-yl)piperazine-1-carboxylate was separated by chiral HPLC (Column: Lux cellulose-4, 0.46×5 cm, 3 μm; Mobile phase: hexanes (0.1% Et₂NH):EtOH=60:40 in 6 min) to afford the title compounds as follows: tert-butyl (R)-4-(3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)chroman-7-yl)piperazine-1-carboxylate as a yellow solid (first eluting isomer, RT=3.87 min, stereochemistry assumed) and tert-butyl (S)-4-(3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)chroman-7-yl)piperazine-1-carboxylate as a yellow solid (second eluting isomer, RT=4.74 min, stereochemistry assumed).

Step 3. (R)-3-Amino-6-methyl-N-(7-(piperazin-1-yl)chroman-3-yl)thieno[2,3-b]pyridine-2-carboxamide

A solution of (R)-4-(3-(3-amino-6-methylthieno[2,3]pyridine-2-carboxamido)chroman-7-yl)piperazine-1-carboxylate (6 mg, 0.01 mmol) and TFA (0.5 mL) in CH₂Cl₂ (2 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by prep-HPLC (Column:)(Bridge Prep C18 OBD, 19×50 mm, 5 μm; Mobile phase A: water (10 mM NH₄HCO₃), B: ACN; Gradient: 5% B to 30% B in 13 min) to give (R)-3-amino-6-methyl-N-(7-(piperazin-1-yl)chroman-3-yl)thieno[2,3-b]pyridine-2-carboxamide as a yellow solid. ¹H NMR (CD₃OD, 400 MHz) δ (ppm): 8.18 (d, J=8.0 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 6.54-6.56 (m, 1H), 6.41 (d, J=2.4 Hz, 1H), 4.40-4.47 (m, 1H), 4.21-4.24 (m, 1H), 3.88-3.93 (m, 1H), 3.07-3.12 (m, 4H), 2.95-3.02 (m, 5H), 2.82-2.88 (m, 1H), 2.62 (s, 3H). MS: (ESI, m/z): 424 [M+H]⁺.

Step 4. (S)-3-Amino-6-methyl-N-(7-(piperazin-1-yl)chroman-3-yl)thieno[2,3-b]pyridine-2-carboxamide

A procedure similar to Step 3 was applied to (S)-4-(3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)chroman-7-yl)piperazine-1-carboxylate (8 mg, 0.02 mmol) to afford (S)-3-amino-6-methyl-N-(7-(piperazin-1-yl)chroman-3-yl)thieno[2,3-b]pyridine-2-carboxamide as a white solid. ¹H NMR (CD₃OD, 300 MHz) δ (ppm): 8.18 (d, J=8.4 Hz, 1H), 7.28 (d, J=8.7 Hz, 1H), 6.96 (d, J=8.7 Hz, 1H), 6.54-6.58 (m, 1H), 6.41 (d, J=2.1 Hz, 1H), 4.39-4.86 (m, 1H), 4.22-4.25 (m, 1H), 3.88-3.96 (m, 1H), 3.04-3.10 (m, 5H), 2.89-3.02 (m, 4H), 2.81-2.87 (m, 1H), 2.63 (s, 3H). MS: (ESI, m/z): 424 [M+H]⁺.

The following examples in Table 9 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Examples 1-1 and 1-2.

TABLE 9 LRMS Example Structure and Compound m/z Number Name [M + H]⁺ ¹H NMR 1-3¹

  N-((3R)-7-(3,8- diazabicyclo[3.2.1]octan-3- yl)chroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2- carboxamide 450 (CD₃OD, 400 MHz) δ (ppm): 8.20 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.44 (dd, J = 2.4, 8.4 Hz, 1H), 6.27 (s, 1H), 4.45-4.40 (m, 1H), 4.23-4.20 (m, 1H), 3.92-3.78 (m, 1H), 3.58-3.56 (m, 2H), 3.41-3.38 (m, 2H), 2.99-2.94 (m, 1H), 2.87-2.80 (m, 3H), 2.63 (s, 3H), 1.89-1.87 (m, 4H). 1-4¹

  N-((3S)-7-(3,8- diazabicyclo[3.2.1]octan-3- yl)chroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2- carboxamide 450 (CD₃OD, 400 MHz) δ (ppm): 8.20 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.44 (dd, J = 2.4, 8.4 Hz, 1H), 6.28 (s, 1H), 4.45-4.40 (m, 1H), 4.23-4.20 (m, 1H), 3.92-3.78 (m, 1H), 3.58-3.56 (m, 2H), 3.41-3.38 (m, 2H), 2.99-2.94 (m, 1H), 2.87-2.80 (m, 3H), 2.63 (s, 3H), 1.89-1.87 (m, 4H). 1-5²

  N-((3R)-7-(3,9- diazabicyclo[3.3.1]nonan-3- yl)chroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2- carboxamide 464 (DMSO-d₆, 400 MHz) δ (ppm): 8.32 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H),. 7.31 (d, J = 8.4 Hz, 1H), 7.21 (s, 2H), 6.91 (d, J = 8.4 Hz, 1H), 6.46 (d, J = 11.2 Hz, 1H), 6.24 (d, J = 2.4 Hz, 1H), 4.26-4.31 (m, 1H), 4.13- 4.16 (m, 1H), 3.77-3.82 (m, 1H), 3.52-3.56 (m, 2H), 3.07 (s, 2H), 2.81- 2.90 (m, 4H), 2.58 (s, 3H), 2.50-2.51 (m, 1H), 2.18-2.24 (m, 1H), 1.70-1.82 (m, 4H), 1.46-1.49 (m, 1H). 1-6²

  N-((3S)-7-(3,9- diazabicyclo[3.3.1]nonan-3- yl)chroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2- carboxamide 464 (DMSO-d₆, 400 MHz) δ (ppm): 8.32 (d, J = 8.4 Hz, 1H),7.51 (br s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.21 (br s, 2H), 6.91 (d, J = 8.4 Hz, 1H), 6.46 (dd, J = 2.0, 8.4 Hz, 1H), 6.24 (s, 1H), 4.31-4.26 (m, 1H), 4.16-4.13 (m, 1H), 3.80 (t, J = 10.0 Hz, 3H), 3.56- 3.52 (m, 2H), 3.08-3.01 (m, 2H), 2.92-2.81 (m, 4H), 2.58 (s, 3H), 2.24- 2.18 (m, 1H), 1.82-1.72 (m, 4H), 1.49-1.46 (m, 1H). 1-7³

  3-amino-N-((R)-7-((2R,3S)-2,3- dimethylpiperazin-1-yl)chroman-3- yl)-6-methylthieno[2,3-b]pyridine-2- carboxamide 452 (CD₃OD, 300 MHz) δ (ppm): 8.20 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.72 (dd, J = 2.1, 8.4 Hz, 1H), 6.57 (s, 1H), 4.47-4.44 (m, 1H), 4.28-4.23 (m, 1H), 3.95-3.89 (m, 1H), 3.07-2.81 (m, 8H), 2.63 (s, 3H), 1.27 (d, J = 6.6 Hz, 3H), 0.97 (d, J = 6.3 Hz, 3H). 1-8³

  3-amino-N-((S)-7-((2R,3S)-2,3- dimethylpiperazin-1-yl)chroman-3- yl)-6-methylthieno[2,3-b]pyridine-2- carboxamide 452 (CD₃OD, 300 MHz) δ (ppm): 8.20 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.72 (dd, J = 2.1, 8.4 Hz, 1H), 6.57 (s, 1H), 4.47-4.44 (m, 1H), 4.28-4.23 (m, 1H), 3.95-3.89 (m, 1H), 3.07-2.81 (m, 8H), 2.63 (s, 3H), 1.27 (d, J = 6.6 Hz, 3H), 0.97 (d, J = 6.3 Hz, 3H). 1-9³

  3-amino-N-((R)-7-((2S,3R)-2,3- dimethylpiperazin-1-yl)chroman-3- yl)-6-methylthieno[2,3-b]pyridine-2- carboxamide 452 (CD₃OD, 300 MHz) δ (ppm): 8.18 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.67 (dd, J = 2.1, 8.1 Hz, 1H), 6.57 (s, 1H), 4.49-4.41 (m, 1H), 4.27-4.23 (m, 1H), 3.97-3.90 (m, 1H), 3.01-2.63 (m, 8H), 2.60 (s, 3H), 1.25 (d, J = 6.6 Hz, 3H), 0.96 (d, J = 6.3 Hz, 3H). 1-10³

  3-amino-N-((S)-7-((2S,3R)-2,3- dimethylpiperazin-1-yl)chroman-3- yl)-6-methylthieno[2,3-b]pyridine-2- carboxamide 452 (CD₃OD, 300 MHz) δ (ppm): 8.20 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 8.1 Hz, 1H), 6.67 (dd, J = 2.4, 8.4 Hz, 1H), 6.57 (s, 1H), 4.49-4.42 (m, 1H), 4.27-4.23 (m, 1H), 3.95-3.89 (m, 1H), 3.07-2.73 (m, 7H), 3.95-3.89 (m, 1H), 3.09-2.67 (m, 8H), 2.63 (s, 3H), 1.24 (d, J = 6.6 Hz, 3H), 0.97 (d, J = 6.3 Hz, 3H). 1-11³

  3-amino-N-((R)-7-((2R,3R)-2,3- dimethylpiperazin-1-yl)chroman-3- yl)-6-methylthieno[2,3-b]pyridine-2- carboxamide 452 (CD₃OD, 300 MHz) δ (ppm): 8.19 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.54 (dd, J = 2.4, 8.4 Hz, 1H), 6.38 (s, 1H), 4.46-4.43 (m, 1H), 4.26-4.22 (m, 1H), 3.94-3.87 (m, 2H), 3.23-2.81 (m, 7H), 2.63 (s, 3H), 1.16 (d, J = 6.9 Hz, 3H), 0.93 (d, J = 6.6 Hz, 3H). 1-12³

  3-amino-N-((S)-7-((2R,3R)-2,3- dimethylpiperazin-1-yl)chroman-3- yl)-6-methylthieno[2,3-b]pyridine-2- carboxamide 452 (CD₃OD, 300 MHz) δ (ppm): 8.20 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 6.97(d, J = 8.4 Hz, 1H), 6.53 (dd, J = 2.4, 8.4 Hz, 1H), 6.39 (s, 1H), 4.46-4.43 (m, 1H), 4.26-4.21 (m, 1H), 3.96-3.89 (m, 2H), 3.22-2.82 (m, 7H), 2.63 (s, 3H), 1.21(d, J = 6.3 Hz, 3H), 0.96 (d, J = 6.6 Hz, 3H). 1-13³

  3-amino-N-((R)-7-((2S,3S)-2,3- dimethylpiperazin-1-yl)chroman-3- yl)-6-methylthieno[2,3-b]pyridine-2- carboxamide 452 (CD₃OD, 300 MHz) δ (ppm): 8.19 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.53 (dd, J = 2.4, 8.4 Hz, 1H), 6.38 (s, 1H), 4.45-4.43 (m, 1H), 4.25-4.21 (m, 1H), 3.96-3.85 (m, 2H), 3.20-2.87 (m, 7H), 2.63 (s, 3H), 1.15 (d, J = 6.9 Hz, 3H), 0.93 (d, J = 6.9 Hz, 3H). 1-14³

  3-amino-N-((S)-7-((2S,3S)-2,3- dimethylpiperazin-1-yl)chroman-3- yl)-6-methylthieno[2,3-b]pyridine-2- carboxamide 452 (CD₃OD, 300 MHz) δ (ppm): 8.19 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.53 (dd, J = 2.4, 8.4 Hz, 1H), 6.38 (s, 1H), 4.45-4.42 (m, 1H), 4.26-4.22 (m, 1H), 3.94-3.85 (m, 2H), 3.20-2.81 (m, 7H), 2.63 (s, 3H), 1.15 (d, J = 6.9 Hz, 3H), 0.92 (d, J = 6.9 Hz, 3H). 1-15⁴

  (R)-3-amino-5-fluoro-6-methyl-N-(7- (piperazin-1-yl)chroman-3- yl)thieno[2,3-b]pyridine-2- carboxamide 442 (DMSO-d₆, 300 MHz) δ (ppm): 8.29 (d, J = 10.5 Hz, 1H), 7.60 (br s, 1H), 7.17 (br s, 2H), 6.90 (d, J = 8.7 Hz, 1H), 6.48 (dd, J = 2.1, 8.7 Hz, 1H), 6.27 (s, 1H), 4.30-4.21 (m, 1H), 4.16- 4.11 (m, 1H), 3.78 (t, J = 9.9 Hz, 1H), 2.97-2.94 (m, 4H), 2.88-2.78 (m, 6H), 2.55 (s, 3H), 2.47 (br s, 1H). 1-16⁴

  (S)-3-amino-5-fluoro-6-methyl-N-(7- (piperazin-1-yl)chroman-3- yl)thieno[2,3-b]pyridine-2- carboxamide (DMSO-d₆, 300 MHz) δ (ppm): 8.29 (d, J = 10.5 Hz, 1H), 7.60 (br s, 1H), 7.17 (br s, 2H), 6.90 (d, J = 8.7 Hz, 1H), 6.48 (dd, J = 2.4, 8.4 Hz, 1H), 6.27 (s, 1H), 4.30-4.21 (m, 1H), 4.16- 4.11 (m, 1H), 3.78 (t, J = 10.2 Hz, 1H), 2.97-2.94 (m, 4H), 2.88-2.78 (m, 6H), 2.55 (s, 3H), 2.46 (br s, 1H). 1-17⁵

  N-((3R)-7-(3,8- diazabicyclo[3.2.1]octan-3- yl)chroman-3-yl)-3-amino-5- fluorothieno[2,3-b]pyridine-2- carboxamide 454 (DMSO-d₆, 300 MHz) δ (ppm): 8.70 (d, J = 2.1 Hz, 1H), 8.42 (dd, J = 3.0, 9.6 Hz, 1H). 7.68 (d, J = 7.5 Hz, 1H), 7.22 (br s, 2H), 6.89 (d, J = 8.7 Hz, 1H), 6.39 (d, J = 6.0 Hz, 1H), 6.18 (s, 1H), 4.32-4.22 (m, 1H), 4.16-4.13 (m, 1H), 3.79 (t, J = 9.6 Hz, 1H), 3.53- 3.51 (m, 2H), 2.86-2.83 (m, 2H), 2.73-2.67 (m, 2H), 2.50-2.49 (m, 3H), 1.68-1.66 (m, 4H). 1-18⁵

  N-((3S)-7-(3,8- diazabicyclo[3.2.1]octan-3- yl)chroman-3-yl)-3-amino-5- fluorothieno[2,3-b]pyridine-2- carboxamide 454 (DMSO-d₆, 300 MHz) δ (ppm): 8.70 (d, J = 2.1 Hz, 1H), 8.42 (dd, J = 3.0, 9.6 Hz, 1H) 7.68 (d, J = 7.2 Hz 1H), 7.22 (br s, 2H), 6.88 (d, J = 8.4 Hz, 1H), 6.38 (d, J = 8.4 Hz, 1H), 6.17 (s, 1H), 4.32-4.22 (m, 1H), 4.16-4.13 (m, 1H), 3.79 (t, J = 9.6 Hz, 1H), 3.53- 3.51 (m, 2H), 2.86-2.83 (m, 2H), 2.73-2.67 (m, 2H), 2.50-2.49 (m, 3H), 1.68-1.66 (m, 4H). 1-19⁶

  N-((3R)-7-(3,8- diazabicyclo[3.2.1]octan-3- yl)chroman-3-yl)-7-amino-3- methylthieno[2,3-b]pyrazine-6- carboxamide 451 (CD₃OD, 300 MHz) δ (ppm): 8.58 (s, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.49- 6.45 (m, 1H), 6.31 (s, 1H), 4.50-4.41 (m, 1H), 4.25-4.22 (m, 1H), 3.96- 3.89 (m, 1H), 3.74-3.72 (m, 2H), 3.54-3.45 (m, 2H), 3.08-2.82 (m, 4H), 2.73 (s, 3H), 1.96-1.86 (m, 4H). 1-20⁶

  N-((3S)-7-(3,8- diazabicyclo[3.2.1]octan-3- yl)chroman-3-yl)-7-amino-3- methylthieno[2,3-b]pyrazine-6- carboxamide 451 (CD₃OD, 300 MHz) δ (ppm): 8.58 (s, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.48- 6.45 (m, 1H), 6.31 (s, 1H), 4.50-4.41 (m, 1H), 4.25-4.22 (m, 1H), 3.96- 3.89 (m, 1H), 3.74-3.72 (m, 2H), 3.54-3.45 (m, 2H), 3.08-2.82 (m, 4H), 2.73 (s, 3H), 1.96-1.86 (m, 4H). 1-21⁷

  (R)-7-amino-3-methyl-N-(7- (piperazin-1-yl)chroman-3- yl)thieno[2,3-b]pyrazine-6- carboxamide 425 (DMSO-d₆, 400 MHz) δ (ppm): 8.64 (s, 1H), 7.79 (br s, 1H), 6.98 (br s, 2H), 6.92 (d, J = 8.4 Hz, 1H), 6.50 (dd, J = 2.4, 8.8 Hz, 1H), 6.29 (s, 1H), 4.33-4.26 (m, 1H), 4.18-4.14 (m, 1H), 3.84-3.79 (m, 1H), 2.98-2.92 (m, 4H), 2.88-2.83 (m, 2H), 2.81-2.79 (m, 4H), 2.65 (s, 3H), 2.39-2.32 (m, 1H). 1-22⁷

  (S)-7-amino-3-methyl-N-(7- (piperazin-1-yl)chroman-3- yl)thieno[2,3-b]pyrazine-6- carboxamide 425 (DMSO-d₆, 400 MHz) δ (ppm): 8.64 (s, 1H), 7.79 (br s, 1H), 6.98 (br s, 2H), 6.92 (d, J = 8.8 Hz, 1H), 6.51 (dd, J = 2.4, 8.4 Hz, 1H), 6.29 (s, 1H), 4.34-4.25 (m, 1H), 4.18-4.15 (m, 1H), 3.84-3.79 (m, 1H), 2.98-2.92 (m, 4H), 2.88-2.83 (m, 2H), 2.81-2.79 (m, 4H), 2.65 (s, 3H), 2.39-2.32 (m, 1H). 1-23⁸

  N-((3R)-7-(3,8- diazabicyclo[3.2.1]octan-3- yl)chroman-3-yl)-6-amino-2- methylthieno[2,3-d]thiazole-5- carboxamide 456 (DMSO-d₆, 400 MHz) δ (ppm): 7.43 (d, J = 7.6 Hz, 1H), 7.14 (br s, 2H), 6.87 (d, J = 8.8 Hz, 1H), 6.37 (dd, J = 2.4, 8.8 Hz, 1H), 6.16 (s, 1H), 4.28- 4.20 (m, 1H), 4.19-4.10 (m, 1H), 3.78-3.73 (m, 1H), 3.50-3.48 (m, 2H), 3.33-3.30 (m, 3H), 2.86-2.68 (m, 5H), 2.51-2.50 (m, 2H), 1.69-1.67 (m, 4H). 1-24⁸

  N-((3S)-7-(3,8- diazabicyclo[3.2.1]octan-3- yl)chroman-3-yl)-6-amino-2- methylthieno[2,3-d]thiazole-5- carboxamide 456 (DMSO-d₆, 400 MHz) δ (ppm): 7.43 (d, J = 7.6 Hz, 1H), 7.14 (br s, 2H), 6.88 (d, J = 8.4 Hz, 1H), 6.37 (dd, J = 2.0, 8.4 Hz, 1H), 6.17 (s, 1H), 4.28- 4.21 (m, 1H), 4.19-4.10 (m, 1H), 3.78-3.73 (m, 1H), 3.50-3.48 (m, 2H), 3.33-3.30 (m, 3H), 2.86-2.68 (m, 5H), 2.51-2.50 (m, 2H), 1.69-1.67 (m, 4H). 1-25⁹

  (R)-6-amino-2-methyl-N-(7- (piperazin-1-yl)chroman-3- yl)thieno[2,3-d]thiazole-5- carboxamide 430 (DMSO-d₆, 300 MHz) δ (ppm): 7.45 (br s, 1H), 7.15 (br s, 2H), 6.92 (d, J = 8.7 Hz, 1H), 6.50 (dd, J = 2.4, 8.4 Hz, 1H), 6.30 (s, 1H), 4.28-4.22 (m, 1H), 4.16-4.12 (m, 1H), 3.78 (t, J = 9.9 Hz, 1H), 3.52-3.49 (m, 1H), 3.02-2.97 (m, 4H), 2.84-2.80 (m, 9H). 1-26⁹

  (S)-6-amino-2-methyl-N-(7- (piperazin-1-yl)chroman-3- yl)thieno[2,3-d]thiazole-5- carboxamide 430 (DMSO-d₆, 300 MHz) δ (ppm): 7.45 (br s, 1H), 7.15 (br s, 2H), 6.92 (d, J = 8.7 Hz, 1H), 6.50 (dd, J = 2.4, 8.7 Hz, 1H), 6.30 (s, 1H), 4.28-4.22 (m, 1H), 4.16-4.12 (m, 1H), 3.78 (t, J = 9.9 Hz, 1H), 3.52-3.49 (m, 1H), 3.02-2.97 (m, 4H), 2.85-2.80 (m, 9H). 1-27¹⁰

  N-((3S)-7-(3,8- diazabicyclo[3.2.1]octan-3- yl)chroman-3-yl)-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5- carboxamide 432 (CD₃OD, 300 MHz) δ (ppm): 8.69 (s, 1H), 8.39 (s, 1H), 7.49 (d, J = 3.6 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.56 (d, J = 3.6 Hz, 1H), 6.42 (dd, J = 2.4, 8.4 Hz, 1H), 6.27 (s, 1H), 4.48-4.21 (m, 4H), 3.97-3.93 (m, 1H), 3.57-3.42 (m, 2H), 3.36-3.31 (m, 2H), 3.05-2.98 (m, 1H), 2.82-2.78 (m, 3H), 1.84-1.82 (m, 4H), 1.42 (t, J = 7.2 Hz, 3H). 1-28¹⁰

  N-((3R)-7-(3,8- diazabicyclo[3.2.1]octan-3- yl)chroman-3-yl)-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5- carboxamide 432 (CD₃OD, 300 MHz) δ (ppm): 8.69 (s, 1H), 8.39 (s, 1H), 7.49 (d, J = 3.6 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.56 (d, J = 3.3 Hz, 1H), 6.43 (dd, J = 2.4, 8.4 Hz, 1H), 6.28 (s, 1H), 4.48-4.21 (m, 4H), 3.97-3.93 (m, 1H), 3.57-3.42 (m, 2H), 3.36-3.31 (m, 2H), 3.05-2.98 (m, 1H), 2.82-2.78 (m, 3H), 1.84-1.82 (m, 4H), 1.42 (t, J = 7.2 Hz, 3H). 1-29¹¹

  N-((3R)-7-(3,8- diazabicyclo[3 .2.1]octan-3-yl)-5- fluorochroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2- carboxamide 468 (CD₃OD, 300 MHz) δ (ppm): 8.20 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 6.24-6.19 (m, 1H), 6.11 (s, 1H), 4.43-4.40 (m, 1H), 4.22-4.19 (m, 1H), 3.94-3.87 (m, 1H), 3.58-3.53 (m, 2H), 3.32-3.29 (m, 2H), 3.11-2.94 ( m, 1H), 2.85-2.81 (m, 2H), 2.76-2.70 (m, 1H), 2.63 (s, 3H), 1.89-1.81 (m, 4H). 1-30¹¹

  N-((3S)-7-(3,8- diazabicyclo[3.2.1]octan-3-yl)-5- fluorochroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2- carboxamide 468 (CD₃OD, 300 MHz) δ (ppm): 8.20 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 6.24-6.19 (m, 1H), 6.12 (s, 1H), 4.43-4.40 (m, 1H), 4.22-4.19 (m, 1H), 3.94-3.87 (m, 1H), 3.58-3.53 (m, 2H), 3.32-3.29 (m, 2H), 3.11-2.94 ( m, 1H), 2.85-2.81 (m, 2H), 2.76-2.71 (m, 1H), 2.63 (s, 3H), 1.91-1.83 (m, 4H). 1-31¹²

  (R)-3-amino-6-methyl-N-(7- (piperazin-1-yl)-6- (trifluoromethoxy)chroman-3- yl)thieno[2,3-b]pyridine-2- carboxamide 508 (DMSO-d₆, 400 MHz) δ (ppm): 8.32 (d, J = 8.4 Hz, 1H), 7.60 (br s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.23 (br s, 2H), 7.03 (s, 1H), 6.49 (s, 1H), 4.40- 4.20 (m, 1H), 4.19-4.17 (m, 1H), 3.89-3.84 (m, 1H), 2.92-2.79 (m, 10H), 2.67 (s, 3H). 1-32¹²

  (S)-3-amino-6-methyl-N-(7- (piperazin-1-yl)-6- (trifluoromethoxy)chroman-3- yl)thieno[2,3-b]pyridine-2- carboxamide 508 (DMSO-d₆, 400 MHz) δ (ppm): 8.32 (d, J = 8.1 Hz, 1H), 7.59 (br s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.23 (br s, 2H), 7.04 (s, 1H), 6.50 (s, 1H), 4.30- 4.20 (m, 1H), 4.19-4.16 (m, 1H), 3.90-3.83 (m, 1H), 2.92-2.79 (m, 10H), 2.58 (s, 3H). 1-33¹³

  (R)-3-amino-N-(8-fluoro-7- (piperazin-1-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 442 (DMSO-d₆, 300 MHz) δ (ppm): 8.21 (d, J = 9 MHz, 1H), 7.31 (d, J = 9 MHz, 1H), 6.82 (d, J = 9 MHz, 1H), 6.62-6.56 (m, 1H), 4.51-4.42 (m, 1H), 4.36-4.30 (m, 1H), 4.31-3.93 (m, 1H), 3.04 (s, 11H), 2.63 (s, 3H). 1-34¹³

  (S)-3-amino-N-(8-fluoro-7- (piperazin-1-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 442 (DMSO-d₆, 300 MHz) δ (ppm): 8.21 (d, J = 9 MHz, 1H), 7.31 (d, J = 9 MHz, 1H), 6.82 (d, J = 9 MHz, 1H), 6.62-6.56 (m, 1H), 4.51-4.42 (m, 1H), 4.36-4.30 (m, 1H), 4.31-3.93 (m, 1H), 3.04 (s, 11H), 2.63 (s, 3H). 1-35¹⁴

  (R)-3-amino-N-(6-fluoro-7- (piperazin-1-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 442 (CD₃OD, 300 MHz) δ (ppm): 8.19 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 6.79 (d, J = 12.6 Hz, 1H), 6.47 (d, J = 7.5 Hz, 1H), 4.45-4.42 (m, 1H), 4.25-4.20(m, 1H), 3.95- 3.88 (m, 1H), 3.06-2.81 (m, 11H), 2.63 (s, 3H). 1-36¹⁴

  (S)-3-amino-N-(6-fluoro-7- (piperazin-1-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 442 (DMSO-d₆, 300 MHz) δ (ppm): 8.20 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 6.83 (d, J = 12.6 Hz, 1H), 6.51 (d, J = 7.5 Hz, 1H), 4.45-4.43 (m, 1H), 4.25-4.20 (m, 1H), 3.96-3.90 (m, 1H), 3.25-2.92 (m, 11H), 2.63 (s, 3H). 1-37¹⁵

  (R)-6-amino-N-(5-fluoro-7- (piperazin-1-yl)chroman-3-yl)-2- methylthieno[2,3-d]thiazole-5- carboxamide 448 (CD₃OD, 300 MHz) δ (ppm): 6.33 (dd, J = 2.4, 12.6 Hz, 1H), 6.24 (s, 1H), 4.40-4.20 (m, 1H), 4.43-4.36 (m, 1H), 4.25-4.21 (m, 1H), 3.93-3.86 (m, 1H), 3.12-3.10 (m, 4H), 3.03-2.96 (m, 5H), 2.81 (s, 3H), 2.75-2.66 (m, 1H). 1-38¹⁵

  (S)-6-amino-N-(5-fluoro-7- (piperazin-1-yl)chroman-3-yl)-2- methylthieno[2,3-d]thiazole-5- carboxamide 448 (CD₃OD, 300 MHz) δ (ppm): 6.34 (dd, J = 2.4, 12.6 Hz, 1H), 6.24 (s, 1H), 4.40-4.20 (m, 1H), 4.43-4.36 (m, 1H), 4.25-4.21 (m, 1H), 3.93-3.86 (m, 1H), 3.12-3.10 (m, 4H), 3.03-2.96 (m, 5H), 2.81 (s, 3H), 2.75-2.66 (m, 1H). 1-39¹⁶

  N-((3R)-7-(3,8- diazabicyclo[3.2.1]octan-3-yl)-5- fluorochroman-3-yl)-6-amino-2- methylthieno[2,3-d]thiazole-5- carboxamide 474 (CD₃OD, 300 MHz) δ (ppm): 6.22 (dd, J = 2.4, 12.9 Hz, 1H), 6.12 (s, 1H), 4.40-4.37 (m, 1H), 4.23-4.18 (m, 1H), 3.91-3.85 (m, 1H), 3.64-3.62 (m, 2H), 3.42-3.31 (m, 2H), 3.11-2.65 (m, 7H), 1.87-1.85 (m, 4H). 1-40¹⁶

  N-((3S)-7-(3,8- diazabicyclo[3.2.1]octan-3-yl)-5- fluorochroman-3-yl)-6-amino-2- methylthieno[2,3-d]thiazole-5- carboxamide 474 (CD₃OD, 300 MHz) δ (ppm): 6.21 (dd, J = 2.4, 12.9 Hz, 1H),6.11 (s, 1H), 4.40-4.37 (m, 1H), 4.23-4.18 (m, 1H), 3.91-3.85 (m, 1H), 3.64-3.62 (m, 2H), 3.32-3.31 (m, 2H), 3.11-2.65 (m, 7H), 1.87-1.85 (m, 4H). 1-41¹⁷

  N-((3S)-7-(3, 6- diazabicyclo[3.1.1]heptan-3-yl)-5- fluorochroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2- carboxamide 454 (DMSO-d₆, 300 MHz) δ (ppm): 8.33 (d, J = 8.7 Hz, 1H). 7.56 (br s, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.23 (br s, 2H), 6.13 (dd, J = 2.1, 12.9 Hz, 1H), 5.96 (s, 1H), 4.34-4.25 (m, 1H), 4.19- 4.15 (m, 1H), 3.87-3.81 (m, 1H), 3.67-3.64 (m, 2H), 3.41-3.32 (m, 4H), 2.90-2.73 (m, 2H), 2.70 (s, 3H), 1.69 (br s, 1H), 1.50-1.45 (m, 1H). 1-42¹⁷

  N-((3R)-7-(3,6- diazabicyclo[3.1.1]heptan-3-yl)-5- fluorochroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2- carboxamide 454 (CD₃OD, 400 MHz) δ (ppm): 8.20 (d, J = 8.0 Hz, 1H). 7.30 (d, J = 8.4 Hz, 1H), 6.13 (dd, J = 2.4, 12.8 Hz, 1H), 6.06 (s, 1H), 4.45-4.40 (m, 1H), 4.25- 4.21 (m, 1H), 3.95-3.87 (m, 3H), 3.55-3.49 (m, 4H), 3.01-2.96 (m, 1H), 2.77-2.70 (m, 2H), 2.65 (s, 3H), 1.68- 1.67(m, 1H). ¹Notes on procedures: In Step 1, the amine Intermediate 13 was used, and purification was by silica gel chromatography (eluting with 2:3 EtOAc/pet. ether). Step 2 chiral HPLC (Column: Chiralpak ID-2, 2 × 25 cm, 5 μm; Mobile phase: 40% EtOH/hexanes for 41 min) afforded Example 1-4 precursor as the first eluting isomer (RT = 3.32 min) and Example 1-3 precursor as the second eluting isomer (RT = 4.42 min). 2Notes on procedures: In Step 1, the amine Intermediate 14-1 was used, and purification was by silica gel chromatography (eluting with 1:1 EtOAc/pet. ether). Step 2 chiral HPLC (Column: Chiralpak IB, 4.6 × 250 mm, 5 μm; Mobile phase A: hexanes (0.1% Et₂NH), B: EtOH; Gradient: 50% B to 50% B in 30 min) afforded Example 1-5 precursor as the first eluting isomer (RT = 3.7 min) and Example 1-6 precursor as the second eluting isomer (RT = 7.1 min). Step 3 purification by prep-HPLC (Column: XBridge Prep Phenyl OBD, 19 × 150 mm, 5 μm; Mobile phase A: Water (0.05% NH₄OH), B: ACN; Gradient: 25% B to 60% B in 7 min). ³Notes on procedures: In Step 1, the amine Intermediate 14-2 was used. Step 2 chiral separation was not performed. Step 3 prep-HPLC isolated Diastereomer Mixture 1 (containing Examples 1-7 thru 1-10, stereochemistry assumed) and Diastereomer Mixture 2 (containing Examples 1-11 thru 1-14, stereochemistry assumed). Further purification of Mixture 1 by chiral HPLC (Column: Chiralpak ID-2, 2 × 25 cm, 5 μm; Mobile phase: 20% IPA/MTBE (0.1% Et₂NH) for 23 min) provided Mixture 1a (RT = 8.9 min, containing Examples 1-7 and 1-8, stereochemistry assumed) and Mixture 1b (RT = 9.5 min, containing Examples 1-9 and 1-10, stereochemistry assumed). Separation of Mixture la (Column: Chiralpak IE, 2 × 25 cm, 5 μm; Mobile phase: 50% EtOH/hexanes for 25 min; Flow rate: 15 mL/min) provided Example 1-7 (RT = 19.1 min, stereochemistry assumed) and Example 1-8 (RT = 23.0 min, stereochemistry assumed). Separation of Mixture 1b (Column: Chiralpak ID-2, 2 × 25 cm, 5 μm; Mobile phase: 20% IPA/MTBE (0.1% Et₂NH) for 23 min) provided Example 1-9 (RT = 14.6 min, stereochemistry assumed) and Example 1-10 (RT = 20.1 min, stereochemistry assumed). Further purification of Mixture 2 by chiral HPLC (Column: Chiralpak ID-2, 2 × 25 cm, 5 μm; Mobile phase: 30% EtOH/MTBE for 26 min; Flow rate: 16 mL/min) provided Mixture 2a (RT = 8.4 min, containing Examples 1-11 and 1-12, stereochemistry assumed), Example 1-13 (RT = 9.5 min, stereochemistry assumed), and Example 1-14 (RT = 10.4 min, stereochemistry assumed). Separation of Mixture 2a (Column: Phenomenex Lux Cellulose-4, AXIA Packed, 2.12 × 25 cm, 5 μm; Mobile Phase: 50% EtOH/Hex (0.1% Et2NH) for 22 min) provided Example 1-11 (RT = 16.0 min, stereochemistry assumed) and Example 1-12 (RT = 19.9 min, stereochemistry assumed). ⁴Notes on procedures: In Step 1, the carboxylic acid Intermediate 16 was used. Step 2 chiral HPLC (Column: Chiralpak IA, 2 × 25 cm, 5 μm; Mobile phase A: hexanes, B: EtOH; Flow rate: 17 mL/min; Gradient: 40% B to 60% B in 23 min) afforded Example 1-15 precursor as the first eluting isomer (RT = 15.9 min) and Example 1-16 precursor as the second eluting isomer (RT = 19.7 min). ⁵Notes on procedures: In Step 1, the carboxylic acid Intermediate 17 and the amine Intermediate 13 were used. Step 2 chiral HPLC (Column: Phenomenex Lux Cellulose-4, AXIA Packed, 2.12 × 25 cm, 5 μm; Mobile Phase : 50% EtOH/hexanes for 15 min) afforded Example 1-17 precursor as the first eluting isomer (RT = 9.3 min) and Example 1-18 precursor as the second eluting isomer (RT = 11.8 min). ⁶Notes on procedures: In Step 1, the amine Intermediate 13 was used. Step 2 chiral HPLC (Column: Chiralpak ID-2, 2 × 25 cm, 5 μm; Mobile phase: 80% MeOH/CH₂Cl₂ for 15 min; Flow rate: 17 mL/min) afforded Example 1-19 precursor as the first eluting isomer (RT = 10.5 min) and Example 1-20 precursor as the second eluting isomer (RT = 12.2 min). ⁷Notes on procedures: Step 2 chiral HPLC (Column: Chiral Art Cellulose-SB, 2 × 25 cm, 5 μm; Mobile phase: 30% EtOH/Hexanes for 30 min) afforded Example 1-21 precursor as the first eluting isomer (RT = 22.2 min) and Example 1-22 precursor as the second eluting isomer (RT = 26.5 min). ⁸Notes on procedures: In Step 1, the carboxylic acid Intermediate 24 and the amine Intermediate 13 were used. Step 2 chiral HPLC (Column: Chiralpak ID-2, 2 × 25 cm, 5 μm; Mobile phase: 50% EtOH/hexanes for 35 min; Flow rate: 14 mL/min) afforded Example 1-23 precursor as the first eluting isomer (RT = 21.6 min) and Example 1-24 precursor as the second eluting isomer (RT = 29.0 min). ⁹Notes on procedures: In Step 1, the carboxylic acid Intermediate 24 was used. Step 2 chiral HPLC (Column: Chiralpak IC, 2 × 25 cm, 5 μm; Mobile phase: 50% EtOH/hexanes for 25 min) afforded Example 1-25 precursor as the first eluting isomer (RT = 15.8 min) and Example 1-26 precursor as the second eluting isomer (RT = 20.4 min). ¹⁰Notes on procedures: In Step 1, the carboxylic acid Intermediate 25 and the amine Intermediate 13 were used. Step 2 chiral HPLC (Column: Chiralpak ID-3, 2 × 25 cm, 5 μm; Mobile phase: 50% iPrOH/hexanes for 10 min) afforded Example 1-27 precursor as the first eluting isomer (RT = 4.5 min) and Example 1-28 precursor as the second eluting isomer (RT = 7.2 min). ¹¹Notes on procedures: In Step 1, the amine Intermediate 15-1 was used. Step 2 chiral HPLC (Column: Chiralpak IA-2, 2 × 25 cm, 5 μm; Mobile phase: 50% EtOH/hexanes for 25 min; Flow rate: 16 mL/min) afforded Example 1-29 precursor as the first eluting isomer (RT = 16.6 min) and Example 1-30 precursor as the second eluting isomer (RT = 21.1 min). ¹²Notes on procedures: In Step 1, the amine Intermediate 15-2 was used; the amide coupling condition of HBTU and Et₃N in DMA was used. Step 2 chiral HPLC (Column: Chiralpak IC, 2 × 25 cm, 5 μm; Mobile phase: 20% EtOH/MTBE) afforded Example 1-31 precursor as the first eluting isomer (RT = 6.9 min) and Example 1-32 precursor as the second eluting isomer (RT = 20.0 min). In Steps 3 and 4, the crude product was treated with NH₃ in MeOH to afford the free base before purification by prep-HPLC. ¹³Notes on procedures: In step 1, the amine Intermediate 4-1 was used. Step 2 chiral HPLC (Column: Chiralpak IC, 2 × 25 cm, 5 μm; Mobile phase: 50% EtOH/hexanes for 22 min; Flow rate: 15 mL/min). Step 3 prep-HPLC (Column: XBridge Shield RP18 OBD, 5 μm, 19 × 150 mm; Mobile phase: Water (with 10 mM NH₄HCO₃) and ACN, gradient (25% ACN up to 65% in 7 min)). ¹⁴Notes on procedures: In step 1, the amine Intermediate 4-2 was used. Step 2 chiral HPLC (Column: Chiralpak IA, 2.12 × 15 cm, 5 μm; Mobile Phase A: hexanes, B: EtOH; Gradient: 0% to 50% B in 17 min). Step 3 prep-HPLC (Column: XBridge C18, 19 × 150 mm, 5 μm; Mobile Phase A:Water (10 mM NH₄HCO₃), B: ACN; Gradient: (10% B to 80% B in 10 min)). ¹⁵Notes on procedures: In step 1 the amine Intermediate 15-3 and the carboxylic acid Intermediate 24 were used. The enantiomers were separated by chiral HPLC using chiral column Chiral Art Cellulose-SB and mobile phase 10% IPA/MTBE to provide the precursor to Example 1-37 as the first eluting isomer and the precursor to Example 1-38 as the second eluting isomer. ¹⁶Notes on procedures: In step 1, the carboxylic acid Intermediate 24 was used. The enantiomers were separated by chiral HPLC using chiral column Chiralpak ID-2 and mobile phase 40% EtOH/hexanes to provide the precursor to Example 1-39 as the first eluting isomer and the precursor to Example 1-40 as the second eluting isomer. ¹⁷Notes on procedures: In step 1, the amine Intermediate 15-3 was used. The enantiomers were separated by chiral HPLC using chiral column Chiralpak IG and mobile phase 50% EtOH/hexanes to provide the precursor to Example 1-41 as the first eluting isomer and the precursor to Example 1-42 as the second eluting isomer.

Step 1. Tert-Butyl 7-((R)-3-(((benzyloxy)carbonyl)amino)chroman-7-yl)-9,9-difluoro-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate

A mixture of benzyl (R)-(7-bromochroman-3-yl)carbamate, Intermediate 2, (400 mg, 1.08 mmol), tert-butyl 9,9-difluoro-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate, Intermediate 32, (288 mg, 1.06 mmol), Pd(dppf)Cl₂—CH₂Cl₂ (90 mg, 0.11 mmol), Xphos (105 mg, 0.22 mmol), and Cs₂CO₃ (1.076 g, 3.30 mmol) in toluene (40 mL) was stirred for 16 h at 100° C. After cooling to room temperature, the reaction was quenched with water (40 mL) and extracted with EtOAc (40 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:4 EtOAc/pet. ether) to give tert-butyl 7-((R)-3-(((benzyloxy)carbonyl)amino)chroman-7-yl)-9,9-difluoro-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate as a yellow oil. MS: (ESI, m/z): 544 [M+H]⁺.

Step 2. Tert-Butyl 7-((R)-3-aminochroman-7-yl)-9,9-difluoro-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate

A mixture of tert-butyl 7-((R)-3-(((benzyloxy)carbonyl)amino)chroman-7-yl)-9,9-difluoro-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (110 mg, 0.19 mmol) and Pd/C (20 mg, 10%) in EtOAc (10 mL) was stirred for 2 h at 30° C. under an atmosphere of hydrogen. The solids were filtered away and the filtrate was concentrated under vacuum to afford tert-butyl 7-((R)-3-aminochroman-7-yl)-9,9-difluoro-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate as a yellow solid. MS: (ESI, m/z): 410 [M+H]⁺.

Step 3. Tert-Butyl 7-((R)-3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)chroman-7-yl)-9,9-difluoro-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate

A solution of tert-butyl 7-((R)-3-aminochroman-7-yl)-9,9-difluoro-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (70 mg, 0.16 mmol), 3-amino-6-methylthieno[2,3-b]pyridine-2-carboxylic acid (43 mg, 0.20 mmol), HOBt (45 mg, 0.33 mmol), EDCI (65 mg, 0.34 mmol), and DIEA (66 mg, 0.51 mmol) in DMF (15 mL) was stirred for 16 h at room temperature. The reaction was quenched by the addition of 25 mL of water. The resulting mixture was extracted with EtOAc (30 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:1 EtOAc/pet. ether) afforded tert-butyl 7-((R)-3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)chroman-7-yl)-9,9-difluoro-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate as a yellow solid. MS: (ESI, m/z): 600 [M+H]⁺.

Step 4. 3-Amino-N-((3R)-7-(9,9-difluoro-3,7-diazabicyclo[3.3.1]nonan-3-yl)chroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide

A solution of tert-butyl 7-((R)-3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)chroman-7-yl)-9,9-difluoro-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (50 mg, 0.08 mmol) and TFA (1 mL) in CH₂Cl₂ (3 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was dissolved in NH₃ (7M in MeOH) (5 mL) and stirred for 1 h. The mixture was concentrated and the crude product was purified by prep-HPLC (Column: XBridge Prep C18 OBD, 19×250 mm, 5 μm; Mobile phase A: water (10 mM NH₄HCO₃), B: ACN; Gradient: 30% B to 50% B in 7 min) to afford 3-amino-N-((3R)-7-(9,9-difluoro-3,7-diazabicyclo[3.3.1]nonan-3-yl)chroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide as a yellow solid. ¹H NMR (CD₃OD, 300 MHz) δ (ppm): 8.19 (d, J=8.1 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 6.64 (dd, J=2.4, 8.4 Hz, 1H), 6.48 (s, 1H), 4.41-4.48 (m, 1H), 4.21-4.25 (m, 1H), 3.82-3.96 (m, 3H), 3.35-3.37 (m, 2H), 3.13-3.19 (m, 4H), 2.80-2.98 (m, 2H), 2.63 (s, 3H), 2.15-2.18 (m, 2H). MS: (ESI, m/z): 500 [M+H]⁺.

The following examples in Table 10 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Example 2-1.

TABLE 10 LRMS Example m/z Number Structure and Compound Name [M + H]⁺ ¹H NMR 2-2¹

  N-((3R)-7-(3,6- diazabicyclo[3.1.1]heptan-3- yl)chroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2- carboxamide 436 (DMSO-d₆, 300 MHz) δ (ppm): 8.32 (d, J = 8.4 Hz, 1H), 7.49 (br s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.21 (br s, 1H), 6.92 (d, J = 8.8 Hz, 1H), 6.29 (dd, J = 2.0, 8.4 Hz, 1H), 6.09 (s, 1H), 4.34-4.24 (m, 1H), 4.15-4.11 (m, 1H), 3.81 (t, J = 10.0 Hz, 1H), 3.71-3.69 (m, 2H), 3.43-3.32 (m, 6H), 2.87-2.83 (m, 2H), 2.58 (s, 3H), 1.49-1.46 (m, 1H). 2-3¹

  N-((3S)-7-(3,6- diazabicyclo[3.1.1]heptan-3- yl)chroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2- carboxamide 436 (DMSO-d₆, 300 MHz) δ (ppm): 8.32 (d, J = 8.4 Hz, 1H), 7.49 (br s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.21 (br s, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.29 (dd, J = 2.4, 8.4 Hz, 1H), 6.09 (s, 1H), 4.34-4.24 (m, 1H), 4.15-4.11 (m, 1H), 3.80 (t, J = 10.0 Hz, 1H), 3.71-3.69 (m, 2H), 3.43-3.32 (m, 6H), 2.87-2.83 (m, 2H), 2.58 (s, 3H), 1.47-1.45 (m, 1H). 2-4²

  3-amino-6-methyl-N-((R)-7-((S)-2- methylpiperazin-1-yl)chroman-3- yl)thieno[2,3-b]pyridine-2- carboxamide 438 (CD₃OD, 300 MHz) δ (ppm): 8.20 (d, J = 8.4 Hz, 1H). 7.30 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.61 (d, J = 8.7 Hz, 1H), 6.46 (s, 1H), 4.48- 4.42 (m, 1H), 4.26-4.22 (m, 1H), 3.94-3.87 (m, 1H), 3.63-3.56 (m, 1H), 3.10-2.75 (m, 8H), 2.63 (s, 3H), 0.98 (d, J = 6.6 Hz,1H). 2-5³

  3-amino-6-methyl-N-((R)-7-((R)-2- methylpiperazin-1-yl)chroman-3- yl)thieno[2,3-b]pyridine-2- carboxamide 438 (CD₃OD, 300 MHz) δ (ppm): 8.20 (d, J = 8.4 Hz, 1H). 7.30 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.61 (d, J = 8.7 Hz, 1H), 6.46 (s, 1H), 4.48- 4.42 (m, 1H), 4.26-4.22 (m, 1H), 3.94-3.87 (m, 1H), 3.63-3.56 (m, 1H), 3.05-2.74 (m, 8H), 2.64 (s, 3H), 0.98 (d, J = 6.6 Hz,1H). 2-6⁴

  N-((3R)-7-(3,8- diazabicyclo[3.2.1]octan-8- yl)chroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2- carboxamide 450 (CD₃OD, 400 MHz) δ (ppm): 8.21 (d, J = 8.4 Hz, 1H). 7.32 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.47 (dd, J = 2.0, 8.4 Hz, 1H), 6.35 (s, 1H), 4.48-4.44 (m, 1H), 4.27-4.23 (m, 1H), 4.11-4.08 (m, 2H), 3.96-3.91 (m, 1H), 3.18-3.15 (m, 2H), 3.02-2.97 (m, 1H), 2.90-2.84 (m, 1H), 2.65 (s, 3H), 2.60- 2.57 (m, 2H), 2.08-1.96 (m, 1H). 2-7⁵

  (R)-N-(7-(2,5-diazaspiro[3.4]octan-5- yl)chroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2- carboxamide 450 (DMSO-d₆, 400 MHz) δ (ppm): 8.32(d, J = 8.0 Hz, 1H), 7.50 (br s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.20 (br s, 2H), 6.91 (d, J = 8.8 Hz, 1H), 6.66 (d, J = 5.6 Hz, 1H), 6.51 (s, 1H), 4.17-4.14 (m, 3H), 3.81 (t, J = 10.0 Hz, 1H), 3.50-3.38 (m, 2H), 3.30- 3.17 (m, 3H), 2.87-2.85 (m, 1H), 2.58 (s, 3H), 2.27-2.20 (m, 3H), 1.78- 1.75(m, 2H). 2-8⁶

  3-amino-6-methyl-N-((R)-7-((S)-3- methylpiperazin-1-yl)chroman-3- yl)thieno[2,3-b]pyridine-2- carboxamide 438 (DMSO-d₆, 300 MHz) δ (ppm): 8.32 (d, J = 8.4 Hz, 1H), 7.52 (br s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.22 (br s, 2H), 6.91 (d, J = 8.4 Hz, 1H), 6.50 (dd, J = 2.4, 8.4 Hz, 1H), 6.29 (s, 1H), 4.31-4.25 (m, 1H), 4.17-4.12 (m, 1H), 3.83-3.76 (m, 1H), 3.44-3.40 (m, 2H), 2.93-2.72 (m, 5H), 2.58 (s, 3H), 2.50- 2.39 (m, 2H), 2.15-2.08 (m, 1H), 1.00 (d, J = 6.3 Hz, 3H). 2-9⁷

  3-amino-6-methyl-N-((R)-7-((R)-3- methylpiperazin-1-yl)chroman-3- yl)thieno[2,3-b]pyridine-2- carboxamide 3H). 438 (DMSO-d₆, 300 MHz) δ (ppm): 8.32 (d, J = 8.4 Hz, 1H), 7.52 (br s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.22 (br s, 2H), 6.91 (d, J = 8.4 Hz, 1H), 6.50 (dd, J = 2.1, 8.4 Hz, 1H), 6.29 (s, 1H), 4.31-4.25 (m, 1H), 4.17-4.12 (m, 1H), 3.83-3.76 (m, 1H), 3.44-3.40 (m, 2H), 2.93-2.72 (m, 5H), 2.58 (s, 3H), 2.51- 2.43 (m, 1H), 2.25 (br s, 1H), 2.15- 2.08 (m, 1H), 1.00 (d, J = 6.3 Hz, 2-10⁸

  (R)-N-(7-(2-oxa-5,8- diazaspiro[3.51nonan-5-yl)chroman- 3-yl)-3-amino-6-methylthieno[2,3- b]pyridine-2-carboxamide 466 (DMSO-d₆, 300 MHz) δ (ppm): 8.32 (d, J = 8.1 Hz, 1H), 7.56 (br s, 1H), 7.31(d, J = 8.1 Hz, 1H), 7.22 (br s, 2H), 6.94 (d, J = 8.4 Hz, 1H),6.27- 6.23 (m, 1H), 6.05(s, 1H), 4.48-4.43 (m, 4H), 4.33-4.14 (m, 2H), 3.85-3.79 (m, 1H), 3.32-3.31 (m, 2H), 3.13-3.08 (m, 4H), 2.90-2.87 (m, 2H), 2.58 (s, 3H). 2-11⁹

  N-((3R)-7-(3,6- diazabicyclo[3.1.1]heptan-3- yl)chroman-3-yl)-7-amino-3- methylthieno[2,3-b]pyrazine-6- carboxamide (DMSO-d₆, 400 MHz) δ (ppm): 8.66 (s, 1H), 7.75(d, J = 7.6 Hz, 1H), 6.98 (br s, 2H), 6.92(d, J = 8.8 Hz, 1H), 6.29 (d, J = 10.8 Hz, 1H), 6.09 (s, 1H), 4.33- 4.28 (m, 1H), 4.16 (d, J = 13.2 Hz, 1H), 3.84-3.79 (m, 1H), 3.68 (d, J = 6.0 Hz, 2H), 3.42-3.32 (m, 4H), 2.88-2.86 (m, 2H), 2.68-2.65 (s, 3H), 2.50-2.48 (m, 1H), 1.48 (m,1H). 2-12⁸

  N-((3R)-7-(3-oxa-7,9- diazabicyclo[3.3.1]nonan-7- yl)chroman-3-yl)-7-amino-3- methylthieno[2,3-b]pyrazine-6- carboxamide 467 (DMSO-d₆, 400 MHz) δ (ppm): 8.66 (s, 1H), 7.77 (d, J = 7.6 Hz, 1H), 6.98 (br s, 2H), 6.92 (d, J = 8.4 Hz, 1H), 6.44-6.41 (m, 1H), 6.22 (s, 1H), 4.34- 4.22 (m, 1H), 4.19-4.11 (m, 1H), 3.85-3.72 (m, 5H), 3.63-3.59 (m, 2H), 2.95-2.86 (m, 6H), 2.68 (s, 3H). 2-13⁸

  N-((3R)-7-(9-oxa-3,7- diazabicyclo[3.3.1]nonan-3- yl)chroman-3-yl)-7-amino-3- methylthieno[2,3-b]pyrazine-6- carboxamide 467 (DMSO-d₆, 400 MHz) δ (ppm): 8.65 (s, 1H), 7.77 (d, J = 7.2 Hz, 1H), 6.98- 6.96 (m, 3H), 6.56 (d, J = 8.0 Hz, 1H), 4.40-4.20 (m, 1H), 4.20-4.10 (m, 1H), 3.86-3.81 (m, 1H), 3.72-3.63 (m, 4H), 3.09-3.05 (m, 2H), 3.01-2.94 (m, 4H), 2.90-2.82 (m, 2H), 2.65 (s, 3H). 2-14¹⁰

  N-((3R)-7-(3,6- diazabicyclo[3.1.1]heptan-3- yl)chroman-3-yl)-3-amino-6- fluorothieno[2,3-b]pyridine-2- carboxamide 440 (DMSO-d₆, 400 MHz) δ (ppm): 8.64 (t, J = 8.0 Hz, 1H). 7.61 (br s, 1H), 7.32 (br s, 2H), 7.27 (d, J = 8.0 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.29 (dd, J = 8.4, 2.0 Hz, 1H), 6.09 (br s, 1H), 4.31-4.27 (m, 1H), 4.17-4.14 (m, 1H), 3.80 (t, J = 10.0 Hz, 1H), 3.72- 3.68 (m, 2H), 3.43-3.33 (m, 4H), 2.51-2.50 (m, 2H), 2.91-2.82 (m, 2H), 1.48-1.46 (m, 1H). 2-15¹¹

  N-((3R)-7-(3,6- diazabicyclo[3.1.1]heptan-3- yl)chroman-3-yl)-3-amino-5-fluoro- 6-methylthieno[2,3-b]pyridine-2- carboxamide 454 (DMSO-d₆, 300 MHz) δ (ppm): 8.31 (d, J = 10.5 Hz, 1H). 7.58 (br s, 1H), 7.18 (br s, 2H), 6.92 (d, J = 8.7 Hz, 1H), 6.28 (dd, J = 2.4, 8.7 Hz, 1H), 6.08 (s, 1H), 4.32-4.26 (m, 1H), 4.17- 4.13 (m, 1H), 3.80 (t, J = 9.9 Hz, 1H), 3.67-3.65 (m, 2H), 3.42-3.33 (m, 4H), 2.92-2.81 (m, 2H), 2.56 (s, 3H), 2.51- 2.44 (m, 1H), 1.57 (br s, 1H), 1.47- 1.44 (m, 1H). 2-16¹²

  (R)-3-amino-5-fluoro-6-methoxy-N- (7-(piperazin-1-yl)chroman-3- yl)thieno[2,3-b]pyridine-2- carboxamide 458 (DMSO-d₆, 300 MHz) δ (ppm): 8.33 (d, J = 11.1 Hz, 1H), 7.48 (br s, 1H), 7.14 (br s, 1H), 6.92 (d, J = 8.7 Hz, 1H), 6.49 (dd, J = 2.4, 8.7 Hz, 1H), 6.29 (s, 1H), 4.27-4.18 (m ,1H), 4.27- 4.12 (m, 1H), 4.03 (s, 1H), 3.79 (t, J = 9.9 Hz, 1H), 2.97-2.94 (m, 4H), 2.86- 2.76 (m, 6H). 2-17¹³

  (R)-3-amino-4,6-dimethyl-N-(7- (piperazin-1-yl)chroman-3- yl)thieno[2,3-b]pyridine-2- carboxamide 438 (DMSO-d₆, 400 MHz) δ (ppm): 7.55(br s, 1H), 7.04 (s, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.86 (br s, 2H), 6.50 (dd, J = 2.4, 8.4 Hz, 1H), 6.29 (s, 1H), 4.31-4.26 (m, 1H), 4.16-4.12 (m, 1H), 3.80 (t, J = 9.9 Hz, 1H), 2.98-2.95 (m, 4H), 2.87-2.78 (m, 6H), 2.72 (s, 3H), 2.50 (s, 3H), 2.25 (br s, 1H). 2-18¹⁴

  N-((3R)-7-(3,6- diazabicyclo[3.1.1]heptan-3- yl)chroman-3-yl)-3-amino-4,6- dimethylthieno[2,3-b]pyridine-2- carboxamide 450 (DMSO-d₆, 300 MHz) δ (ppm): 7.53 (br s, 1H), 7.04 (s, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.86 (br s, 2H), 6.28 (dd, J = 2.1, 8.4 Hz, 1H), 6.09 (s, 1H), 4.32-4.13 (m, 2H), 3.80 (t, J = 9.9 Hz, 1H), 3.67-3.65 (m, 2H), 3.42-3.33 (m, 4H), 2.88-2.85 (m, 2H), 2.72 (s, 3H), 2.50 (s, 3H), 2.46-2.44 (m, 1H), 1.55 (br s, 1H), 1.47-1.44 (m, 1H). 2-19¹³

  3-amino-N-((3R)-7-(9,9-difluoro-3,7- diazabicyclo[3.3.1]nonan-3- yl)chroman-3-yl)-4,6- dimethylthieno[2,3-b]pyridine-2- carboxamide 480 (DMSO-d₆, 300 MHz) δ (ppm): 7.57 (br s, 1H), 7.04 (s, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.87 (br s, 2H), 6.57 (dd, J = 2.0, 8.0 Hz, 1H), 6.38 (s, 1H), 4.31-4.14 (m, 2H), 3.83-3.78 (m, 3H), 3.26-3.22 (m, 2H), 3.10-3.07 (m, 2H), 3.02-2.83 (m, 4H), 2.72 (s, 3H), 2.50 (s, 3H), 2.16-2.12 (m, 2H). 2-20¹⁵

  N-((3R)-7-(9-oxa-3,7- diazabicyclo[3.3.1]nonan-3- yl)chroman-3-yl)-3-amino-4,6- dimethylthieno[2,3-b]pyridine-2- carboxamide 480 (DMSO-d₆, 300 MHz) δ (ppm): 7.56 (br s, 1H), 7.05 (s, 1H), 6.97 (d, J = 8.7 Hz, 1H), 6.87 (br s, 2H), 6.57 (dd, J = 2.4, 8.7 Hz, 1H), 6.37 (s, 1H), 4.33-4.27 (m, 1H), 4.19-4.14 (m, 1H), 3.82 (t, J = 9.9 Hz, 1H), 3.72-3.64 (m, 4H), 3.11-2.94 (m, 6H), 2.90-2.86 (m, 2H), 2.73 (s, 3H), 2.50 (s, 3H). 2-21¹⁶

  N-((3R)-7-(3,6- diazabicyclo[3.1.1]heptan-3- yl)chroman-3-yl)-3-amino-6-methyl- 4-(trifluoromethypthieno[2,3- b]pyridine-2-carboxamide (DMSO-d₆, 300 MHz) δ (ppm): 7.90 (s, 1H), 7.60 (br s, 1H), 6.92 (d, J = 6.3 Hz, 1H), 6.68 (br s, 2H), 6.32- 6.30 (m, 1H), 6.10 (s, 1H), 4.32-4.15 (m, 2H), 3.85-3.67 (m, 3H), 3.32-3.30 (m, 3H), 2.87-2.70 (m, 3H), 2.50 (s, 3H), 1.65-1.45 (m, 2H). 2-22¹⁷

  3-amino-N-((3R)-7-(9,9-difluoro-3,7- diazabicyclo[3.3.1]nonan-3- yl)chroman-3-yl)-6-methyl-4- (trifluoromethyl)thieno[2,3- b]pyridine-2-carboxamide (DMSO-d₆, 300 MHz) δ (ppm): 7.92 (d, J = 7.2 Hz, 1H), 7.76 (s,1H), 6.96 (d, J = 8.1 Hz, 1H), 6.68-6.57 (m, 3H), 6.38 (s, 1H), 4.33-4.27 (m, 1H), 4.19- 4.16 (m, 1H), 3.86-3.83 (m, 3H), 3.26-3.21 (m, 2H), 3.11-3.07 (m, 2H), 2.96-2.87 (m, 4H), 2.70 (s, 3H), 2.11- 2.04 (m, 1H). 2-23¹⁶

  N-((3R)-7-(9-oxa-3,7- diazabicyclo[3.3.1]nonan-3- yl)chroman-3-yl)-3-amino-6-methyl- 4-(trifluoromethyl)thieno[2,3- b]pyridine-2-carboxamide 534 (CD₃OD, 400 MHz) δ (ppm): 7.66 (s, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.66- 6.63 (m, 1H), 6.50 (s, 1H), 4.50-4.43 (m, 1H), 4.27-4.23 (m, 1H), 3.97-3.89 (m, 3H), 3.72-3.69 (m, 2H), 3.29-3.27 (m, 2H), 3.19-3.12 (m, 4H), 3.04-2.98 (m, 1H), 2.94-2.83 (m, 1H), 2.72 (s, 3H). 2-24¹⁸

  N-((3R)-7-(3,8- diazabicyclo[3.2.1]octan-3- yl)chroman-3-yl)-2′,3′-dihydro-1′H- spiro[cyclopropane-1,4′- [1,8]naphthyridine]-6′-carboxamide 446 (DMSO-d₆, 300 MHz) δ (ppm): 8.29 (s, 1H), 7.95 (d, J = 7.2 Hz, 1H), 7.31 (d, J = 1.8 Hz, 1H), 7.21 (s, 1H), 6.87 (d, J = 8.7 Hz, 1H), 6.37 (dd, J = 2.1, 8.7 Hz, 1H), 6.16 (s, 1H), 4.24-4.11 (m, 2H), 3.75-3.68 (m, 1H), 3.47-3.44 (m, 2H), 3.37-3.34 (m, 2H), 3.30-3.28 (m, 2H), 2.89-2.72 (m, 2H), 2.67-2.64 (m, 2H), 2.27-2.21 (m, 1H), 1.64-1.60 (m, 6H), 1.02-0.98 (m, 2H), 0.76-0.73 (m, 2H). 2-25¹⁹

  N-((3R)-7-(3,8- diazabicyclo[3.2.1]octan-3- yl)chroman-3-yl)-6- (benzylamino)nicotinamide 470 (CD₃OD, 300 MHz) δ (ppm): 8.47 (s, 1H), 7.83 (br s, 1H), 7.32-7.24 (m, 5H), 6.91(d, J = 8.4 Hz, 1H), 6.52 (d, J = 8.4 Hz, 1H), 6.45 (dd, J = 2.4, 8.4 Hz, 1H), 6.27 (s, 1H), 4.55 (s, 2H), 4.42-4.34 (m, 1H), 4.24-4.18 (m, 1H), 3.93-3.89 (m, 1H), 3.63-3.61 (m, 2H), 3.43-3.39 (m, 2H), 3.02-2.94 (m, 1H), 2.85-2.81(m, 3H), 1.87-1.86 (m, 4H). 2-26²⁰

  N-((3R)-7-(3,6- diazabicyclo[3.1.1]heptan-3- yl)chroman-3-yl)-6-amino-2- methylthieno[2,3-d]thiazole-5- carboxamide 442 (DMSO-d₆, 400 MHz) δ (ppm): 7.41 (br s, 1H), 7.14 (br s, 2H), 6.91 (d, J = 8.4 Hz, 1H), 6.28 (dd, J = 2.4, 8.4 Hz, 1H), 6.09 (s, 1H), 4.26-4.21 (m, 1H), 4.18-4.05 (m, 2H), 3.77 (t, J = 9.9 Hz, 1H), 3.68-3.67 (m, 2H), 3.43-3.56 (m, 4H), 3.18-3.16 (m, 2H), 2.84- 2.81 (m, 2H), 2.79 (s, 3H), 1.47 (d, J = 8.1 Hz, 1H). 2-27²⁰

  N-((3R)-7-(3,9- diazabicyclo[3.3.1]nonan-3- yl)chroman-3-yl)-6-amino-2- methylthieno[2,3-dithiazole-5- carboxamide 470 (CD₃OD, 300 MHz) δ (ppm): 6.96 (d, J = 8.1 Hz, 1H), 6.54 (dd, J = 2.4, 8.4 Hz, 1H), 6.38 (s, 1H), 4.42-4.38 (m, 1H), 4.25-4.21 (m, 1H), 3.92-3.85 (m, 1H), 3.78-3.74 (m, 2H), 3.46-3.44 (m, 2H), 3.15-3.06 (m, 2H), 3.01-2.84 (m, 2H), 2.79 (s, 3H), 2.50-2.40 (m, 1H), 2.07-1.96 (m, 4H), 1.58-1.48 (m, 1H). 2-28²¹

  6-amino-N-((3R)-7-(9,9-difluoro-3,7- diazabicyclo[3.3.1]nonan-3- yl)chroman-3-yl)-2-methylthieno[2,3- d]thiazole-5-carboxamide 506 (CD₃OD, 300 MHz) δ (ppm): 6.98 (d, J = 8.1 Hz, 1H), 6.65 (dd, J = 2.4, 8.4 Hz, 1H), 6.49 (s, 1H), 4.48-4.41 (m, 1H), 4.28-4.22 (m, 1H), 3.95-3.85 (m, 3H), 3.34-3.14 (m, 6H), 3.10-2.83 (m, 5H), 2.20-2.10 (m, 2H). 2-29-HU 22

  N-((3R)-7-(3,9- diazabicyclo[3.3.1]nonan-3- yl)chroman-3-yl)-7-ethyl-7H- pyrrolo[2,3-c]pyridazine-3- carboxamide 447 (DMSO-d₆, 300 MHz) δ (ppm): 8.89 (d, J = 7.8 Hz, 1H), 8.46(s, 1H), 8.10 (br s, 1H), 6.94 (d, J = 8.7 Hz, 1H), 6.75 (d, J = 3.3 Hz, 1H), 6.50 (d, J = 6.3 Hz, 1H), 6.32 (s, 1H), 4.52-4.49 (m, 4H), 4.20-4.04 (m, 2H), 3.60-3.57 (m, 2H), 3.16-3.14 (m, 1H), 2.97-2.89 (m, 5H), 2.54-2.51(m, 2H), 1.85-1.78 (m, 4H), 1.47 (t, J = 7.2 Hz, 3H). 2-30²³

  N-((3R)-7-(9,9-difluoro-3,7- diazabicyclo[3.3.1]nonan-3- yl)chroman-3-yl)-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5- carboxamide 482 (DMSO-d₆, 400 MHz) δ (ppm): 8.76 (s, 1H), 8.65-8.47 (m, 2H), 7.81 (br s, 1H), 7.09-6.97 (m, 1H), 6.62-6.59 (m, 2H), 6.39 (s, 1H), 4.67-4.07 (m, 4H), 3.89-3.61 (m, 3H), 3.33-2.83 (m, 8H), 2.15-2.06 (m, 2H), 1.39 (t, J = 6.4 Hz, 3H). 2-31²⁴

  (R)-3-amino-N-(8-cyano-5-fluoro-7- (piperazin-1-yl)chroman-3-yl)-4,6- dimethylthieno[2,3-b]pyridine-2- carboxamide 481 (DMSO-d₆, 300 MHz) δ (ppm): 7.74(d, J = 6.6 Hz, 1H), 7.04 (s, 1H), 6.89 (s, 2H), 6.55 (d, J = 11.7 Hz, 1H), 4.36-4.32 (m, 2H), 4.12-4.08 (m, 1H), 3.06-3.03 (m, 4H),2.91-2.89(m, 6H), 2.84-2.72 (s, 3H), 2.51-2.50 (m, 3H). 2-23²⁵

  (R)-3-amino-N-(6-cyano-5-fluoro-7- (piperazin-1-yl)chroman-3-yl)-4,6- dimethylthieno[2,3-b]pyridine-2- carboxamide 481 (DMSO-d₆, 300 MHz) δ (ppm): 7.69(d, J = 6.6 Hz, 1H), 7.04 (s, 1H), 6.88 (s, 2H), 6.36 (s, 1H), 4.36-4.32 (m, 2H), 4.12-4.08 (m, 1H), 3.06-3.03 (m, 5H),2.91-2.89(m, 5H), 2.84-2.72 (s, 3H), 2.51-2.50 (m, 3H). 2-33²⁶

  3-amino-N-((3R)-6-cyano-7-(9,9- difluoro-3,7- diazabicyclo[3.3.1]nonan-3- yl)chroman-3-yl)-6-methylthieno[2,3- b]pyridine-2-carboxamide 525 (DMSO-d₆, 300 MHz) δ (ppm): 8.33 (d, J = 8.4 Hz, 1H). 7.61 (br s, 1H), 7.57 (s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.23 (br s, 2H), 6.62 (s, 1H), 4.30- 4.25 (m, 2H), 3.96 (t, J = 10.2 Hz, 1H), 3.65-3.57 (m, 2H), 3.38-3.25 (m, 5H), 3.08-2.94 (m, 4H), 2.58 (s, 3H), 2.14-2.07 (m, 2H). 2-34²⁷

  (S)-7-amino-3-methyl-N-(7-methyl- 6-(piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)thieno[2,3- b]pyrazine-6-carboxamide 437 (CDCl₃, 300 MHz) δ (ppm): 8.46 (s, 1H), 6.93 (s, 1H), 6.80 (s, 1H), 4.43- 4.40 (m, 1H), 3.41-3.32 (m, 4H), 3.18-3.10 (m, 5H), 2.97-2.84 (m, 3H), 2.73-2.63 (m, 5H), 2.31-2.10 (m, 5H), 1.95-1.85 (m, 1H). 2-35²⁷

  (R)-7-amino-3-methyl-N-(7-methyl- 6-(piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)thieno[2,3- b]pyrazine-6-carboxamide 437 (CDCl₃, 300 MHz) δ (ppm): 8.47 (s, 1H), 6.94 (s, 1H), 6.81 (s, 1H), 4.42- 4.40 (m, 1H), 3.40-3.32 (m, 4H), 3.18-3.10 (m, 5H), 2.98-2.84 (m, 3H), 2.74-2.63 (m, 5H), 2.29-2.10 (m, 5H), 1.94-1.85 (m, 1H) 2-36²⁷

  (S)-7-amino-3-methyl-N-(5-methyl- 6-(piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)thieno[2,3- b]pyrazine-6-carboxamide 437 (CD₃OD, 300 MHz) δ (ppm): 8.58 (s, 1H), 6.92 (s, 2H), 4.28-4.18 (m, 1H), 3.09-3.00 (m, 5H), 2.95-2.75 (m, 7H), 2.69 (s, 3H), 2.25-2.19 (m, 4H),1.92- 1.79 (m, 1H). 2-37²⁷

  (R)-7-amino-3-methyl-N-(5-methyl- 6-(piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)thieno [2,3- b]pyrazine-6-carboxamide 437 (CD₃OD, 300 MHz) (ppm): 8.59 (s, 1H), 6.93 (s, 2H), 4.28-4.18 (m, 1H), 3.12-3.00 (m, 5H), 2.99-2.79 (m, 7H), 2.76 (s, 3H), 2.27-2.19 (m, 4H),1.92- 1.79 (m, 1H). 2-38²⁸

  3-amino-N-((R)-7-((3S,4S)-3-amino- 4-(methoxy-d3)pyrrolidin-1- yl)chroman-3-yl)-6-methylthieno[2,3- b]pyridine-2-carboxamide 457 not determined ¹Notes on procedures: In Step 1, RuPhos Pd G3/RuPhos was used as the catalyst/ligand system; the bromide Intermediate 3 was used for Example 2-3. In Step 4, NH3 treatment was not performed; prep-HPLC conditions (Column: XBridge Prep C18 OBD, 19 × 150 mm, 5 μm; Mobile phase A: water (0.05% NH₄OH), B: ACN; Gradient: 25% B to 55% B in 7 min) were used. ²Notes on procedures: In Step 4, NH₃ treatment was not performed; prep-HPLC conditions (Column: XBridge Prep C18 OBD, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mM NH₄HCO₃ + 0.1% NH₄OH), B: ACN; Gradient: 15% B to 50% B in 7 min) were used. ³Notes on procedures: In Step 1, the reaction was heated by microwave irradiation for 1 h at 140° C. In Step 4, prep-HPLC conditions (Column: XBridge Shield RP18 OBD, 19 × 150 mm, 5 μm; Mobile phase A: Water (10 mM NH₄HCO₃), B: ACN; Gradient: 18% B to 58% B in 7 min) were used. ⁴Notes on procedures: In Step 4, NH₃ treatment was not performed; prep-HPLC conditions (Column: XBridge Prep Phenyl OBD, 19 × 150 mm, 5 μm; Mobile phase A: Water (0.05% NH₄OH), B: MeOH; Gradient: 45% B to 75% B in 12 min) were used. ⁵Notes on procedures: In Step 1, RuPhos Pd G3/RuPhos was used as the catalyst/ligand system. ⁶Notes on procedures: In Step 3, purification was by reverse phase chromatography (Column: C18 silica gel; Mobile phase A: Water (10 mM NH₄HCO₃), B: ACN; Gradient: 0% B to 100% B in 35 min). In Step 4, NH₃ treatment was not performed; prep-HPLC conditions (Column: XBridge Prep C18 OBD, 19 × 150 mm, 5 μm; Mobile phase A: Water (0.05% NH₄OH), B: ACN; Gradient: 15% B to 65% B in 7 min) were used. ⁷Notes on procedures: In Step 4, prep-HPLC conditions (Column: XBridge Prep C18 OBD, 19 × 250 mm, 10 μm; Mobile phase A: water (10 mM NH₄HCO₃), B: ACN; Gradient: 30% B to 50% B in 7 min) were used. ⁸Notes on procedures: In Step 1, RuPhos Pd G3/RuPhos was used as the catalyst/ligand system. In Step 3, the amide coupling condition of HBTU and Et₃N in DMA was used. ⁹Notes on procedures: In Step 1, RuPhos Pd G3/RuPhos was used as the catalyst/ligand system. In Step 3, the amide coupling condition of HBTU and Et₃N in DMA was used. ¹⁰Notes on procedures: In Step 1, RuPhos Pd G3/RuPhos was used as the catalyst/ligand system. In Step 3, the carboxylic acid Intermediate 18 and the amide coupling condition of HBTU and Et₃N in DMA were used. In Step 4, NH₃ treatment was not performed. ¹¹Notes on procedures: In Step 1, RuPhos Pd G3/RuPhos was used as the catalyst/ligand system. In Step 3, the carboxylic acid Intermediate 16 and the amide coupling condition of HBTU and Et₃N in DMA were used. ¹²Notes on procedures: In Step 3, the carboxylic acid Intermediate 20 and the amide coupling condition of HBTU and Et₃N in DMA were used. ¹³Notes on procedures: In Step 3, the carboxylic acid Intermediate 21 was used. ¹⁴Notes on procedures: In Step 1, RuPhos Pd G3/RuPhos was used as the catalyst/ligand system. In Step 3, the carboxylic acid Intermediate 21 and the amide coupling condition of HBTU and Et₃N in DMA were used. ¹⁵Notes on procedures: In Step 1, RuPhos Pd G3/RuPhos was used as the catalyst/ligand system. In Step 3, the carboxylic acid Intermediate 21 and the amide coupling condition of HBTU and Et₃N in DMA were used. ¹⁶Notes on procedures: In Step 1, RuPhos Pd G3/RuPhos was used as the catalyst/ligand system. In Step 3, the carboxylic acid Intermediate 22 and the amide coupling condition of HBTU and Et₃N in DMA were used. ¹⁷Notes on procedures: In Step 3, the carboxylic acid Intermediate 22 and the amide coupling condition of HBTU and Et₃N in DMA were used. ¹⁸Notes on procedures: In Step 3, the carboxylic acid Intermediate 29 and the amide coupling condition of HBTU and Et₃N in DMA were used. In Step 4, NH₃ treatment was not performed. ¹⁹Notes on procedures: In Step 3, the carboxylic acid Intermediate 31 was used. In Step 4, prep-HPLC conditions (Column: XBridge Shield RP18 OBD, 19 × 150 mm, 5 μm; Mobile phase A: Water (10 mM NH₄HCO₃), B: ACN; Gradient: 32% B to 62% B in 7 min) were used. ²⁰Notes on procedures: In Step 1, RuPhos Pd G3/RuPhos was used as the catalyst/ligand system. In Step 3, the carboxylic acid Intermediate 24 was used. In Step 4, NH₃ treatment was not performed; prep-HPLC conditions (Column: XBridge Shield RP18 OBD, 19 × 150 mm, Sum; Mobile phase A: Water (0.05% NH₄OH), B: ACN; Gradient: 25% B to 50% B in 7 min) were used. ²¹Notes on procedures: In Step 3, the carboxylic acid Intermediate 24 and the amide coupling condition of HBTU and Et₃N in DMA were used; purification was by reverse phase chromatography (Column: C18 silica gel; Mobile phase A: Water (0.1% formic acid), B: ACN; Gradient: 0% B to 100% B in 40 min). ²²Notes on procedures: In Step 1, RuPhos Pd G3/RuPhos was used as the catalyst/ligand system. In Step 3, the carboxylic acid Intermediate 26 was used; purification was by reverse phase chromatography (Column: C18 silica gel; Mobile phase A: Water (0.05% TFA), B: ACN; Gradient: 0% B to 70% B in 40 min). In Step 4, NH₃ treatment was not performed; prep-HPLC conditions (Column: XBridge Shield RP18 OBD, 19 × 150 mm, Sum; Mobile phase A: Water (0.05% NH₄OH), B: ACN; Gradient: 35% B to 50% B in 8 min) were used. ²³Notes on procedures: In Step 3, the carboxylic acid Intermediate 25 and the amide coupling condition of HBTU and Et₃N in DMA were used; purification was by reverse phase chromatography (Column: C18 silica gel; Mobile phase A: Water (0.1% formic acid), B: ACN; Gradient: 0% B to 100% B in 40 min). ²⁴Notes on procedures: The amine Intermediate 7-2 and the carboxylic acid Intermediate 21 were used. In the amide coupling step, HBTU was used as the coupling reagent with Et₃N as the base in DMA solvent. The resulting amide was purified by prep-HPLC: Column: C18 silica gel; Mobile phase, A: 10 mM NH₄HCO₃ in H₂O, B: ACN (0% to 60% B in 30 min). After the boc-deprotection step, the resulting amine was purified by prep-HPLC: Column: XBridge Prep C18 OBD Column, 19 × 150 mm 5 μm; mobile phase: water (0.05% NH₄OH) and ACN; gradient: 25% to 55% ACN over 8 min. ²⁵Notes on procedures: The amine Intermediate 7-1 and the carboxylic acid Intermediate 21 were used. In the amide coupling step, HBTU was used as the coupling reagent with Et₃N as the base in DMA solvent. The resulting amide was purified by prep-HPLC: Column: C18 silica gel; Mobile phase A: 10 mM NH₄HCO₃ in H₂O, B: ACN; gradient: 0 to 60% B in 30 min. After the boc-deprotection step, the resulting amine was purified by prep-HPLC: Column: XBridge Shield RP18 OBD, Sum, 19 × 150 mm; Mobile phase: water (0.05% NH₄OH) and ACN; gradient: 20% to 50% ACN over 11 min. ²⁶Notes on procedures: In the amide coupling step, HBTU was used as the coupling reagent with Et₃N as the base in DMA solvent. The resulting amide was purified by silica gel chromatography (ethyl acetate/pet. ether, 1:1). After the boc-deprotection the crude TFA salt was treated with 7M NH₃ in methanol, concentrated and purified by prep-HPLC: Column: X Bridge C18, 19 × 150 mm, 5 μm; Mobile Phase A: water (10 mM NH₄HCO₃), B: ACN; gradient: 10% B to 80% B in 10 min. ²⁷Notes on procedures: In Step 1, the bromides Intermediates 11-2 thru 11-5 were used. Pd₂(dba)₃/Xphos was used as the catalyst/ligand system. ²⁸Notes on procedures: In Step 1, the amine Intermediate 49 was used. In the coupling reaction, Xphos Pd G3 was used as the catalyst system, Cs₂CO₃ as the base, and 1,4-dioxane as the solvent. In Step 3, the amide coupling was accomplished with HATU and Et₃N in DMA at 50° C. In Step 4, the boc-deprotection was accomplished with HCl in dioxane/EtOAc.

Example 3-1. 3-Amino-N—((R)-7-((3S,4S)-3-amino-4-methoxypyrrolidin-1-yl)chroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide and Example 3-2. 3-Amino-N—((R)-7-((3R,4R)-3-amino-4-methoxypyrrolidin-1-yl)chroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide

Step 1. Benzyl ((3R)-7-(3-((tert-butoxycarbonyl)amino)-4-methoxypyrrolidin-1-yl)chroman-3-yl)carbamate

A mixture of benzyl (R)-(7-bromochroman-3-yl)carbamate, Intermediate 2, (170 mg, 0.47 mmol), tert-butyl N-(4-methoxypyrrolidin-3-yl)carbamate, Intermediate 35, (100 mg, 0.46 mmol), RuPhos Pd G3 (38 mg, 0.05 mmol), RuPhos (23 mg, 0.05 mmol), and Cs₂CO₃ (300 mg, 0.92 mmol) in toluene (10 mL) was stirred for 2 h at 95° C. After cooling to room temperature, the reaction was poured into water (20 mL). The resulting mixture was extracted with DCM (2×50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel column (eluting with 1:1 EtOAc/pet. ether) afforded benzyl ((3R)-7-(3-((tert-butoxycarbonyl)amino)-4-methoxypyrrolidin-1-yl)chroman-3-yl)carbamate as a white solid. MS: (ESI, m/z): 498 [M+H]⁺.

Step 2. Tert-Butyl (1-((R)-3-aminochroman-7-yl)-4-methoxypyrrolidin-3-yl)carbamate

A mixture of benzyl ((3R)-7-(3-((tert-butoxycarbonyl)amino)-4-methoxypyrrolidin-1-yl)chroman-3-yl)carbamate (80 mg, 0.16 mmol) and Pd/C (80 mg, 10%) in EtOAc (5 mL) was stirred for 3 h at room temperature under an atmosphere of hydrogen. The solids were filtered away and washed with EtOAc (10 mL×3). The filtrate was concentrated under vacuum to afford tert-butyl (1-((R)-3-aminochroman-7-yl)-4-methoxypyrrolidin-3-yl)carbamate as a colorless oil. MS: (ESI, m/z): 364 [M+H]⁺.

Step 3. Tert-Butyl (1-((R)-3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)chroman-7-yl)-4-methoxypyrrolidin-3-yl)carbamate

A solution of tert-butyl (1-((R)-3-aminochroman-7-yl)-4-methoxypyrrolidin-3-yl)carbamate (40 mg, 0.11 mmol), 3-amino-6-methylthieno[2,3-b]pyridine-2-carboxylic acid (23 mg, 0.11 mmol), Et₃N (39 mg, 0.39 mmol), and HBTU (50 mg, 0.13 mmol) in DMA (2 mL) was stirred for 30 min at room temperature. Purification by reverse phase chromatography (Column: C₁₈ silica gel; Mobile phase A: water (10 mM NH₄HCO₃), B: ACN; Gradient: 10% to 80% B over 10 min) afforded tert-butyl (1-((R)-3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)chroman-7-yl)-4-methoxypyrrolidin-3-yl)carbamate as a white solid. MS: (ESI, m/z): 554 [M+H]⁺.

Step 4. 3-Amino-N-((3R)-7-(3-amino-4-methoxypyrrolidin-1-yl)chroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide

A solution of tert-butyl (1-((R)-3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)chroman-7-yl)-4-methoxypyrrolidin-3-yl)carbamate (45 mg, 0.08 mmol) and TFA (1 mL) in CH₂Cl₂ (3 mL) was stirred for 30 min at room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by reverse phase chromatography (Column: C₁₈ silica gel; Mobile phase A: water (10 mM NH₄HCO₃), B: ACN; Gradient: 10% to 80% B over 10 min) to afford 3-amino-N-((3R)-7-(3-amino-4-methoxypyrrolidin-1-yl)chroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide as a colorless oil. MS: (ESI, m/z): 454 [M+H]⁺.

Step 5. Amino-N—((R)-7-((3S,4S)-3-amino-4-methoxypyrrolidin-1-yl)chroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide and 3-Amino-N—((R)-7-((3R,4R)-3-amino-4-methoxypyrrolidin-1-yl)chroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide

The racemic mixture of 3-amino-N-((3R)-7-(3-amino-4-methoxypyrrolidin-1-yl)chroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide (35 mg, 0.077 mmol) was separated by chiral HPLC (Column: Chiralpak IE, 2×25 cm, 5 μm; Mobile phase: 50% EtOH/MTBE (0.1% Et₂NH) for 28 min; Flow rate: 16 mL/min) to afford the title compounds as follows:

Amino-N—((R)-7-((3S,4S)-3-amino-4-methoxypyrrolidin-1-yl)chroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide as a yellow solid (first eluting isomer, RT=13.5 min). ¹H NMR (DMSO-d₆, 300 MHz) δ (ppm): 8.32 (d, J=8.4 Hz, 1H). 7.49 (br s, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.21 (br s, 2H), 6.87 (d, J=8.4 Hz, 1H), 6.12-6.08 (br s, 1H), 5.91 (s, 1H), 4.31-4.21 (m, 1H), 4.16-4.11 (m, 1H), 3.79 (t, J=9.9 Hz, 1H), 3.63-3.62 (m, 1H), 3.51-3.46 (m, 1H), 3.42-3.32 (m, 2H), 2.93 (s, 3H), 3.13-3.09 (m, 1H), 2.91-2.82 (m, 3H), 2.58 (s, 3H), 2.12-1.96 (m, 2H). MS: (ESI, m/z): 454 [M+H]⁺;

and amino-N—((R)-7-((3R,4R)-3-amino-4-methoxypyrrolidin-1-yl)chroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide as a yellow solid (second eluting isomer, RT=20.2 min). ¹H NMR (DMSO-d₆, 300 MHz) δ (ppm): 8.32 (d, J=8.1 Hz, 1H). 7.49 (br s, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.21 (br s, 2H), 6.86 (d, J=8.4 Hz, 1H), 6.11-6.08 (br s, 1H), 5.91 (s, 1H), 4.31-4.21 (m, 1H), 4.16-4.11 (m, 1H), 3.79 (t, J=9.9 Hz, 1H), 3.63-3.62 (m, 1H), 3.51-3.46 (m, 1H), 3.42-3.32 (m, 2H), 2.93 (s, 3H), 3.13-3.09 (m, 1H), 2.91-2.81 (m, 3H), 2.58 (s, 3H), 2.12-1.96 (m, 2H). MS: (ESI, m/z): 454 [M+H]⁺.

Example 3-1. 3-Amino-N—((R)-7-((3S,4S)-3-amino-4-methoxypyrrolidin-1-yl)chroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide

Method 2.

Amino-N—((R)-7-((3S,4S)-3-amino-4-methoxypyrrolidin-1-yl)chroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide can also be prepared from tert-butyl ((3S,4S)-4-methoxypyrrolidin-3-yl)carbamate, Intermediate 36, using procedures similar to Method 1, without need for the Step 5 chiral separation.

The following examples in Table 11 were prepared using standard chemical manipulations and procedures similar to Method 1 for the preparation of Examples 3-1 and 3-2.

TABLE 11 LRMS Example m/z Number Structure and Compound Name [M+H]⁺ ¹H NMR 3-3¹

  3-amino-N-((R)-7-((S)-3-amino-3- (trifluoromethyl)piperidin-1- yl)chroman-3-yl)-6-methylthieno[2,3- b]pyridine-2-carboxamide 506 (CD₃OD, 400 MHz) δ (ppm): 8.20 (d, J = 8.4 Hz, 1H). 7.31 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.60 (dd, J = 2.4, 8.0 Hz, 1H), 6.47 (s, 1H), 4.47-4.45 (m, 1H), 4.27-4.24 (m, 1H), 3.96-3.91 (m, 1H), 3.55-3.52 (m, 1H), 3.44-3.41 (m, 1H), 2.99-2.98 (m, 1H), 2.91-2.83 (m, 2H), 2.67-2.61 (m, 4H), 2.08-1.94 (m, 1H), 1.81-1.77 (m, 3H). 3-4¹

  3-amino-N-((R)-7-((R)-3-amino-3- (trifluoromethyl)piperidin-1- yl)chroman-3-yl)-6-methylthieno[2,3- b]pyridine-2-carboxamide 506 (CD₃OD, 400 MHz) δ (ppm): 8.32 (d, J = 8.4 Hz, 1H). 7.52 (br s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.22 (br s, 2H), 6.94 (d, J = 8.4 Hz, 1H), 6.55 (dd, J = 2.4, 8.4 Hz, 1H), 6.37 (s, 1H), 4.31- 4.27 (m, 1H), 4.18-4.14 (m, 1H), 3.81 (t, J = 9.6 Hz, 1H), 3.47-3.44 (m, 1H), 3.34-3.31 (m, 1H), 2.88-2.78 (m, 3H), 2.64-2.59 (m, 4H), 2.01 (br s, 2H), 1.94-1.90 (m, 1H), 1.66-1.64 (m, 3H). 3-5²

  3-amino-N-((R)-7-((3R,4S)-3-amino- 4-fluoropyrrolidin-1-yl)chroman-3- yl)-6-methylthieno[2,3-b]pyridine-2- carboxamide 442 (DMSO-d₆, 400 MHz) δ (ppm): 8.32 (d, J = 8.0 Hz, 1H). 7.48 (br s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.20 (br s, 2H), 6.90 (d, J = 8.4 Hz, 1H), 6.11 (dd, J = 2.0, 8.4 Hz, 1H), 5.93 (s, 1H), 4.96 (d, J = 54.1 Hz, 1H), 4.33-4.26 (m, 1H), 4.16-4.08 (m, 1H), 3.79 (t, J = 10.0 Hz, 1H), 3.65-3.37 (m, 6H), 3.02-2.90 (m, 1H), 3.86-3.79 (m, 2H), 2.58 (s, 3H). 3-6²

  3-amino-N-((R)-7-((3S,4R)-3-amino- 4-fluoropyrrolidin-1-yl)chroman-3- yl)-6-methylthieno[2,3-b]pyridine-2- carboxamide 442 (DMSO-d₆, 400 MHz) δ (ppm): 8.32 (d, J = 8.0 Hz, 1H). 7.48 (br s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.20 (br s, 2H), 6.90 (d, J = 8.4 Hz, 1H), 6.12 (dd, J = 2.0, 8.4 Hz, 1H), 5.94 (s, 1H), 5.17-5.01 (m, 1H), 4.33-4.26 (m, 1H), 4.16-4.08 (m, 1H), 3.80 (t, J = 10.0 Hz, 1H), 3.68-3.31 (m, 6H), 3.02- 2.90 (m, 1H), 3.86-3.79 (m, 2H), 2.58 (s, 3H). 3-7³

  3-amino-N-((R)-7-((3S,4S)-3-amino- 4-fluoropyrrolidin-1-yl)chroman-3- yl)-6-methylthieno[2,3-b]pyridine-2- carboxamide 442 (DMSO-d₆, 400 MHz) δ (ppm): 8.32 (d, J = 8.0 Hz, 1H). 7.48 (br s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.20 (br s, 2H), 6.89 (d, J = 8.4 Hz, 1H), 6.13 (dd, J = 2.0, 8.4 Hz, 1H), 5.95 (s, 1H), 4.96 (d, J = 52.4 Hz, 1H), 4.33-4.26 (m, 1H), 4.16-4.08 (m, 1H), 3.80 (t, J = 10.0 Hz, 1H), 3.68-3.55 (m, 2H), 3.50-3.42 (m, 1H), 3.41-3.35 (m, 1H), 3.17 (br s, 2H), 3.02-2.90 (m, 1H), 3.86-3.79 (m, 2H), 2.58 (s, 3H). 3-8³

  3-amino-N-((R)-7-((3R,4R)-3-amino- 4-fluoropyrrolidin-1-yl)chroman-3- yl)-6-methylthieno[2,3-b]pyridine-2- carboxamide 442 (DMSO-d₆, 400 MHz) δ (ppm): 8.32 (d, J = 8.0 Hz, 1H). 7.48 (br s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.20 (br s, 2H), 6.89 (d, J = 8.4 Hz, 1H), 6.13 (dd, J = 2.0, 8.4 Hz, 1H), 5.96 (s, 1H), 4.96 (d, J = 52.8 Hz, 1H), 4.33-4.26 (m, 1H), 4.16-4.08 (m, 1H), 3.80 (t, J = 10.0 Hz, 1H), 3.68-3.55 (m, 2H), 3.50-3.42 (m, 1H), 3.41-3.35 (m, 1H), 3.17 (br s, 2H), 3.02-2.90 (m, 1H), 3.86-3.79 (m, 2H), 2.58 (s, 3H). 3-9⁴

  3-amino-N-((R)-7-((3R,4R)-3-amino- 4-(trifluoromethoxy)pyrrolidin-1- yl)chroman-3-yl)-6-methylthieno[2,3- b]pyridine-2-carboxamide 508 (DMSO-d₆, 300 MHz) δ (ppm): 8.32 (d, J = 8.4 Hz, 1H), 7.51 (brs, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.22 (br s, 2H), 6.89 (d, J = 8.4 Hz, 1H), 6.14 (dd, J = 2.4, 8.4 Hz, 1H), 5.96 (s, 1H), 4.69-4.68 (m, 1H), 4.17-4.12 (m, 2H), 3.83-3.43 (m, 6H), 2.98-2.83 (m, 4H), 2.58 (s, 3H). 3-10⁴

  3-amino-N-((R)-7-((3S,4S)-3-amino- 4-(trifluoromethoxy)pyrrolidin-1- yl)chroman-3-yl)-6-methylthieno[2,3- b]pyridine-2-carboxamide 508 (DMSO-d₆, 300 MHz) δ (ppm): 8.32 (d, J = 8.4 Hz, 1H), 7.51 (brs, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.22 (br s, 2H), 6.89 (d, J = 8.4 Hz, 1H), 6.14 (dd, J = 2.4, 8.4 Hz, 1H), 5.96 (s, 1H), 4.69-4.68 (m, 1H), 4.17-4.12 (m, 2H), 3.83-3.42 (m, 6H), 2.98-2.83 (m, 4H), 2.58 (s, 3H). 3-11⁵

  3-amino-6-methyl-N-((R)-7-((R)-3- (trifluoromethyl)piperazin-1- yl)chroman-3-yl)thieno[2,3- b]pyridine-2-carboxamide 492 (DMSO-d₆, 400 MHz) δ (ppm): 8.32 (d, J = 8.4 Hz, 1H), 7.50 (br s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.20 (brs, 2H), 6.95 (d, J = 8.4 Hz, 1H), 6.54 (dd, J = 2.4, 8.4 Hz, 1H), 6.35 (s, 1H), 4.35-4.24 (m, 1H), 4.17-4.14 (m, 1H), 3.82 (t, J = 10.0 Hz, 1H), 3.55-3.31 (m, 3H), 3.00-2.97 (m, 1H), 2.88-2.75 (m, 4H), 2.69-2.62 (m, 2H), 2.58 (s, 3H). 3-12⁵

  3-amino-6-methyl-N-((R)-7-((S)-3- (trifluoromethyl)piperazin-1- yl)chroman-3-yl)thieno[2,3- b]pyridine-2-carboxamide 492 (DMSO-d₆, 400 MHz) δ (ppm): 8.32 (d, J = 8.4 Hz, 1H), 7.50 (br s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.20 (brs, 2H), 6.95 (d, J = 8.4 Hz, 1H), 6.54 (dd, J = 2.4, 8.4 Hz, 1H), 6.35 (s, 1H), 4.35-4.24 (m, 1H), 4.17-4.14 (m, 1H), 3.82 (t, J = 10.0 Hz, 1H), 3.55-3.31 (m, 3H), 3.00-2.97 (m, 1H), 2.88-2.75 (m, 4H), 2.69-2.62 (m, 2H), 2.58 (s, 3H). 3-13⁶

  N-((R)-7-((S)-2,7- diazaspiro[4.5]decan-2-yl)chroman-3- yl)-3-amino-6-methylthieno[2,3- b]pyridine-2-carboxamide 478 (DMSO-d₆, 300 MHz) δ (ppm): 8.32 (d, J = 8.1 Hz, 1H), 7.47 (brs, 1H), 7.31(d, J = 8.1 Hz, 1H), 7.20 (br s, 2H), 6.86 (d, J = 8.4 Hz, 1H), 6.11 (d, J = 2.1, 8.4 Hz, 1H), 5.91 (s, 1H), 4.27-4.15 (m, 1H), 4.14-4.11 (m, 1H), 3.78 (t, J = 9.9 Hz, 1H), 3.22-3.17 (m, 3H), 2.92-2.83 (m, 3H), 2.82-2.56 (m, 7H), 1.92-1.88 (m, 1H), 1.70-1.66 (m, 1H), 1.65-1.44 (m, 4H). 3-14⁶

  N-((R)-7-((R)-2,7- diazaspiro[4.5]decan-2-yl)chroman-3- yl)-3-amino-6-methylthieno[2,3- b]pyridine-2-carboxamide 478 (DMSO-d₆, 300 MHz) δ (ppm): 8.32 (d, J = 8.4 Hz, 1H), 7.47 (br s, 1H), 7.31(d, J = 8.4 Hz, 1H), 7.20 (br s, 2H), 6.86 (d, J = 8.4 Hz, 1H), 6.12 (d, J = 2.4, 8.4 Hz, 1H), 5.92 (s, 1H), 4.27-4.15 (m, 1H), 4.14-4.11 (m, 1H), 3.78 (t, J = 9.9 Hz, 1H), 3.22-3.17 (m, 3H), 2.92-2.83 (m, 3H), 2.82-2.56 (m, 7H), 1.92-1.88 (m, 1H), 1.70-1.66 (m, 1H), 1.65-1.44 (m, 4H). 3-15⁷

  (1aS,7bR)-N-((3R)-7-(3,8- diazabicyclo[3.2.l]octan-3- yl)chroman-3-yl)-1a,2,3,7b- tetrahydro-1H- cyclopropa[c][1,8]naphthyridine-6- carboxamide 432 (CD₃OD, 300 MHz) δ (ppm): 8.21 (s, 1H), 7.85 (s, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.45 (d, J = 2.4, 8.4 Hz, 1H), 6.30 (s, 1H), 4.43-4.38 (m, 1H), 4.23-4.19 (m, 1H), 3.94-3.88 (m, 1H), 3.72-3.68 (m, 2H), 3.51-3.42 (m, 4H), 3.10-2.88 (m, 1H), 2.85-2.82 (m, 3H), 1.99-1.90 (m, 5H), 1.79-1.75 (m, 1H), 1.08-0.97 (m, 2H). 3-16⁷

  (1aR,7bS)-N-((3R)-7-(3,8- diazabicyclo[3.2.1]octan-3- yl)chroman-3-yl)-1a,2,3,7b- tetrahydro-1H- cyclopropa[c][1,8]naphthyridine-6- carboxamide 432 (CD₃OD, 300 MHz) δ (ppm): 8.21 (s, 1H), 7.85 (s, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.46 (dd, J = 2.4, 8.4 Hz, 1H), 6.30 (s, 1H), 4.41-4.38 (m, 1H), 4.23-4.19 (m, 1H), 3.94-3.88 (m, 1H), 3.72-3.69 (m, 2H), 3.51-3.42 (m, 4H), 3.10-2.88 (m, 1H), 2.85-2.82 (m, 3H), 1.99-1.90 (m, 5H), 1.79-1.75 (m, 1H), 1.08-0.97 (m, 2H). 3-17⁸

  3-amino-N-[(3R)-6,8-difluoro-7- (piperazin-1-yl)-3,4-dihydro-2H-1- benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide 460 (DMSO-d₆, 400 MHz) δ (ppm): 8.33 (d, J = 8.4 Hz, 1H), 7.63(d, J = 7.6 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.24 (br s, 2H), 6.80 (d, J = 11.2 Hz, 1H), 4.43-4.29 (m, 1H), 4.25-4.22 (m, 1H), 3.90-3.85 (m, 1H), 2.99-2.92 (m, 6H), 2.78-2.76 (m, 4H), 2.58 (s, 3H). 3-18⁸

  3-amino-N-[(3S)-6,8-difluoro-7- (piperazin-1-yl)-3,4-dihydro-2H-1- benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide 460 (DMSO-d₆, 400 MHz) δ (ppm): 8.33 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.23 (br s, 2H), 6.81 (d, J = 10.8 Hz, 1H), 4.36-4.28 (m, 1H), 4.26-4.22 (m, 1H), 3.91-3.86 (m, 1H), 3.09-3.03 (m, 4H), 2.95-2.88 (m, 2H), 2.84-2.82 (m, 4H), 2.58 (s, 3H). ¹Notes on procedures: In Step 1, the amine Intermediate 37 was used; Pd(dppf)Cl₂—CHCl₂/Xphos was used as the catalyst/ligand system. In Step 3, purification was by prep-HPLC (Column: XBridge Prep C18 OBD, 19 × 150 mm, 5 μm; Mobile phase A: water (10 mM NH₄HCO₃), B: ACN; Gradient: 20% B to 50% B in 8 min). In Step 5, chiral HPLC (Column: Chiral Art Cellulose-SB, 2 × 25 cm, 5 μm; Mobile phase: 20% EtOH/MTBE for 10 min) provided Example 3-3 (RT = 6.2 min, stereochemistry assumed) and Example 3-4 (RT = 7.9 min, stereochemistry assumed). ²Notes on procedures: In Step 4, the crude product was treated with NH₃ (7M in MeOH) to provide the free base. In Step 5, chiral HPLC (Column: Chiralpak IA, 2 × 25 cm, 5 μm; Mobile phase A: hexanes/CH₂Cl₂ = 3:1, B: EtOH (0.1% EtNH); Flow rate: 14 mL/min; Gradient: hold 50% B in 25 min) provided Example 3-5 (RT = 16.5 min, stereochemistry assumed) and Example 3-6 (RT = 21.5 min, stereochemistry assumed). ³Notes on procedures: In Step 4, the crude product was treated with NH₃ (7M in MeOH) to provide the free base. In Step 5, chiral HPLC (Column: Chiralpak IG, 2 × 25 cm, 5 μm; Mobile phase: 80% MeOH (0.1% IPA)/CH₂Cl₂ for 13.5 min; Flow rate: 18 mL/min) provided Example 3-7 (RT = 8.6 min, stereochemistry assumed) and Example 3-8 (RT = 10.6 min, stereochemistry assumed). ⁴Notes on procedures: In Step 1, the amine Intermediate 38 was used. In Step 4, purification was by prep-HPLC (Column: XBridge Prep C18 OBD, 30 × 150 mm, 5 μm; Mobile phase A: water (0.05% NH₄OH), B: ACN; Gradient: 15% B to 60% B in 7 min). In Step 5, the chiral column Chiralpak IC, 2 × 25 cm, 5 μm was used to provide Example 3-9 (RT = 7.1 min, stereochemistry assumed) and Example 3-10 (RT = 8.9 min, stereochemistry assumed). ⁵Notes on procedures: In Step 3, the amide coupling condition of HOBt, EDCI, and DIEA in DMF was used. In Step 5, purification by chiral HPLC (Column: Chiralpak IA, 2 × 25 cm, 5 μm; Mobile phase: 50% EtOH/Hexanes (0.1% Et₂NH) for 23 min; Flow rate: 15 mL/min) provided Example 13-11 (RT = 14.6 min, stereochemistry assumed) and Example 13-12 (RT = 17.4 min, stereochemistry assumed). ⁶Notes on procedures: In Step 3, the amide coupling condition of HOBt, EDCI, and DIEA in DMA was used. Step 5 chiral separation was not performed. Instead, chiral separation was performed on the products of Step 3: chiral HPLC (Column: Chiralpak IG, 20 × 250 mm, 5 μm; Mobile phase: 30% EtOH/MTBE for 12 min) provided the precursor to Example 3-13 (RT = 6.8 min, stereochemistry assumed) and the precursor to Example 3-14 (RT = 9.2 min, stereochemistry assumed). ⁷Notes on procedures: In Step 1, Pd(dppf)Cl₂—CH₂Cl₂/Xphos was used as the catalyst/ligand system. In Step 3, the carboxylic acid Intermediate 30 was used; the reverse phase chromatography was performed with 0% to 100% water (0.1% formic acid)/ACN over 30 min. In Step 4, HCl (4M in dioxane) was used. In Step 5, purification by chiral HPLC (Column: Chiralpak IG, 2 × 25 cm, 5 μm; Mobile phase: 30% MeOH (0.1% Et₂NH)/CH₂Cl₂ for 15 min) provided Example 13-15 (RT = 9.5 min, stereochemistry assumed) and Example 13-16 (RT = 11.0 min, stereochemistry assumed). ⁸Notes on procedures: In Step 1, the bromide Intermediate 50 was used. The coupling reaction was accomplished using the precatalyst tBuXphos Pd G3 and the phosphazene base P₂-Et in DMSO at 25° C. In Step 5, chiral separation was performed with the chiral column Chiralpak IC and mobile phase 50% EtOH/hexanes (0.1% Et₂NH).

In Step 5, chiral separation was performed with the chiral column Chiralpak IC and mobile phase 50% EtOH/hexanes (0.1% Et₂NH).

Example 4-1. (R)—N-(7-(2-oxa-5,8-diazaspiro[3.5]nonan-8-yl)chroman-3-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide

Step 1. Benzyl (R)-(7-(5-benzyl-2-oxa-5,8-diazaspiro[3.5]nonan-8-yl)chroman-3-yl)carbamate

A mixture of benzyl (R)-(7-bromochroman-3-yl)carbamate, Intermediate 2, (166 mg, 0.44 mmol), 5-benzyl-2-oxa-5,8-diazaspiro[3.5]nonane, Intermediate 33, (100 mg, 0.44 mmol), RuPhos Pd G3 (38 mg, 0.05 mmol), RuPhos (21 mg, 0.05 mmol), and Cs₂CO₃ (300 mg, 0.92 mmol) in toluene (5 mL) was stirred for 16 h at 95° C. After cooling to room temperature, the reaction was poured into 10 mL of water and was extracted with DCM (2×20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with 2:1 EtOAc/pet. ether) afforded benzyl (R)-(7-(5-benzyl-2-oxa-5,8-diazaspiro[3.5]nonan-8-yl)chroman-3-yl)carbamate as a white solid. MS (ESI, m/z): 500 [M+H]⁺.

Step 2. (R)-7-(2-Oxa-5,8-diazaspiro[3.5]nonan-8-yl)chroman-3-amine

A mixture of benzyl (R)-(7-(5-benzyl-2-oxa-5,8-diazaspiro[3.5]nonan-8-yl)chroman-3-yl)carbamate (80 mg, 0.15 mmol) and Pd/C (100 mg, 10%) in EtOAc (5 mL) was stirred for 2 h at room temperature under an atmosphere of hydrogen. The solid was filtered out and washed with MeOH (3×10 mL). The combined filtrate was concentrated under vacuum to give (R)-7-(2-oxa-5,8-diazaspiro[3.5]nonan-8-yl)chroman-3-amine as a light yellow oil. MS (ESI, m/z): 276 [M+H]⁺.

Step 3. (R)—N-(7-(2-Oxa-5,8-diazaspiro[3.5]nonan-8-yl)chroman-3-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide

A solution of (R)-7-(2-oxa-5,8-diazaspiro[3.5]nonan-8-yl)chroman-3-amine (20 mg, 0.07 mmol), 3-amino-6-methylthieno[2,3-b]pyridine-2-carboxylic acid (18 mg, 0.08 mmol), Et₃N (33 mg, 0.33 mmol), and HBTU (42 mg, 0.11 mmol) in DMA (1 mL) was stirred for 30 min at room temperature. Purification by prep-HPLC (Column: X Bridge C18, 19×150 mm, 5 μm; Mobile phase A: water (10 mM NH₄HCO₃), B: ACN; Gradient: 10% B to 80% B in 30 min) afforded (R)—N-(7-(2-oxa-5,8-diazaspiro[3.5]nonan-8-yl)chroman-3-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide as a white solid. ¹H-NMR (CD₃OD, 300 MHz) δ (ppm): 8.20 (d, J=8.4 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 6.62-6.59 (m, 1H), 6.46 (s, 1H), 4.53-4.44 (m, 5H), 4.26-4.21 (m, 1H), 3.95-3.91 (m, 1H), 3.31-3.29 (m, 2H), 3.03-2.91 (m, 3H), 2.89-2.88 (m, 3H), 2.63 (s, 3H). MS (ESI, m/z): 466 [M+H]⁺.

Example 5-1. (R)-3-amino-N-(7-(4,4-difluoropiperidin-1-yl)chroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide

Step 1. Benzyl (R)-(7-(4,4-difluoropiperidin-1-yl)chroman-3-yl)carbamate

A mixture of benzyl (R)-(7-bromochroman-3-yl)carbamate, Intermediate 2, (100 mg, 0.28 mmol), 4,4-difluoropiperidine (42 mg, 0.35 mmol), RuPhos Pd G3 (23 mg, 0.03 mmol), RuPhos (15 mg, 0.03 mmol), and Cs₂CO₃ (225 mg, 0.69 mmol) in toluene (30 mL) was stirred for 1 h at 100° C. After cooling to room temperature, the reaction was poured into water (10 mL). The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (2×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel column (eluting with 1:3 EtOAc/pet. ether) afforded benzyl (R)-(7-(4,4-difluoropiperidin-1-yl)chroman-3-yl)carbamate as an off-white solid. MS: (ESI, m/z): 403 [M+H]⁺.

Step 2. (R)-7-(4,4-Difluoropiperidin-1-yl)chroman-3-amine

A mixture of benzyl (R)-(7-(4,4-difluoropiperidin-1-yl)chroman-3-yl)carbamate (98 mg, 0.24 mmol) and Pd/C (50 mg, 10%) in EtOAc (10 mL) was stirred for 2 h at 30° C. under an atmosphere of hydrogen. The solids were filtered away and the filtrate was concentrated under vacuum to afford 60 mg of (R)-7-(4,4-difluoropiperidin-1-yl)chroman-3-amine as a pale yellow oil. MS: (ESI, m/z): 269 [M+H]⁺.

Step 3. (R)-3-Amino-N-(7-(4,4-difluoropiperidin-1-yl)chroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide

A solution of (R)-7-(4,4-difluoropiperidin-1-yl)chroman-3-amine (60 mg, 0.22 mmol), 3-amino-6-methylthieno[2,3-b]pyridine-2-carboxylic acid (58 mg, 0.28 mmol), Et₃N (90 mg, 0.89 mmol), and HBTU (106 mg, 0.28 mmol) in DMA (2 mL) was stirred for 30 min at room temperature. Purification by prep-HPLC (Column: XBridge Prep C18 OBD, 30×150 mm, 5 μm; Mobile phase A: water (10 mM NH₄HCO₃), B: ACN; Gradient: 40% B to 60% B in 7 min) afforded (R)-3-amino-N-(7-(4,4-difluoropiperidin-1-yl)chroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide as a yellow solid. ¹H NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.32 (d, J=8.0 Hz, 1H), 7.52 (br s, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.21 (br s, 2H), 6.95 (d, J=8.4 Hz, 1H), 6.57 (d, J=8.4 Hz, 1H), 6.41 (s, 1H), 4.31-4.27 (m, 1H), 4.18-4.14 (m, 1H), 3.82 (t, J=10.0 Hz, 1H), 3.28-3.25 (m, 4H), 2.92-2.83 (m, 2H), 2.58 (s, 3H), 2.09-1.97 (m, 4H). MS: (ESI, m/z): 459 [M+H]⁺.

The following examples in Table 12 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Example 5-1.

TABLE 12 LRMS Example m/z Number Structure and Compound Name [M + H]⁺ ¹H NMR 5-2¹

473 (DMSO-d₆, 300 MHz) δ(ppm): 8.33 (d, J = 8.4 Hz, 1H), 7.55 (br s, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.22 (br s, 2H), 6.98 (d, J = 8.7 Hz, 1H), 6.59 (dd, J = 2.4, 8.4 Hz, 1H), 6.45 (s, 1H), 4.32-4.27 (m, 1H), 4.19-4.15 (m, 1H), 3.82 (t, J = 9.9 Hz, 1H), 3.77- 3.72 (m, 4H), 3.11-3.04 (m, 4H), 2.94- 2.83 (m, 2H), 2.58 (s, 3H). (R)-3-amino-N-(7-(1,1- dioxidothiomorpholino)chroman-3- yl)-6-methylthieno[2,3-b]pyridine-2- carboxamide 5-3¹

479 (DMSO-d₆, 400 MHz) δ(ppm): 8.32 (d, J = 8.4 Hz, 1H), 7.52 (br s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.24 (s, 1H), 7.21 (br s, 2H), 6.92 (d, J = 8.0 Hz, 1H), 6.09 (dd, J = 2.4, 8.4 Hz, 1H), 5.95 (s, 1H), 4.33-4.26 (m, 1H), 4.16- 4.12 (m, 1H), 4.08-4.05 (m, 2H), 3.80 (t, J = 10.0 Hz, 1H), 3.75-3.73 (m, 2H), 2.87-2.84 (m, 2H), 2.58 (s, 3H). (R)-3-amino-N-(7-(3-hydroxy-3- (trifluoromethyl)azetidin-1- yl)chroman-3-yl)-6-methylthieno[2,3- b]pyridine-2-carboxamide 5-4 

501 (DMSO-d₆, 300 MHz) δ(ppm): 8.33 (d, J = 8.4 Hz, 1H). 7.51 (br s, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.22 (br s, 2H), 6.93 (d, J = 8.4 Hz, 1H), 6.45 (dd, J = 2.4, 11.6 Hz, 1H), 6.24 (s, 1H), 4.30-4.23 (m, 1H), 4.18-4.15 (m, 1H), 4.07-4.01 (m, 2H), 3.94-3.77 (m, 5H), 3.15-3.12 (m, 2H), 2.88-2.85 (m, 2H), 2.59 (s, 3H), 2.35-2.28 (m, 2H). 3-amino-N-((3R)-7-(9,9-difluoro-3- oxa-7-azabicyclo[3.3.1]nonan-7- yl)chroman-3-yl)-6-methylthieno[2,3- b]pyridine-2-carboxamide ¹Notes on procedures: In Step 3, the Xbridge Shield RP18 OBD column was used for the prep-HPLC purification.

Example 6-1. (R)-1-(3-(3-Amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)chroman-7-yl)piperidine-4-carboxylic Acid

Step 1. Ethyl (R)-1-(3-(((benzyloxy)carbonyl)amino)chroman-7-yl)piperidine-4-carboxylate

A mixture of benzyl (R)-(7-bromochroman-3-yl)carbamate, Intermediate 2, (200 mg, 0.52 mmol), ethyl piperidine-4-carboxylate (130 mg, 0.79 mmol), RuPhos Pd G3 (44 mg, 0.05 mmol), RuPhos (24 mg, 0.05 mmol), and Cs₂CO₃ (513 mg, 1.57 mmol) in toluene (30 mL) was stirred for 2 h at 90° C. After cooling to room temperature, the solids were filtered out and the filtrate was concentrated under vacuum. Purification by silica gel column (eluting with 1:1 EtOAc/pet. ether) afforded ethyl (R)-1-(3-(((benzyloxy)carbonyl)amino)chroman-7-yl)piperidine-4-carboxylate as a yellow solid. MS: (ESI, m/z): 439 [M+H]⁺.

Step 2. Ethyl (R)-1-(3-aminochroman-7-yl)piperidine-4-carboxylate

A mixture of ethyl (R)-1-(3-(((benzyloxy)carbonyl)amino)chroman-7-yl)piperidine-4-carboxylate (180 mg, 0.32 mmol) and Pd/C (50 mg, 10%) in EtOAc (5 mL) was stirred for 2 h at room temperature under an atmosphere of hydrogen. The solids were filtered away and the filtrate was concentrated under vacuum to afford ethyl (R)-1-(3-aminochroman-7-yl)piperidine-4-carboxylate as a yellow oil. MS: (ESI, m/z): 305 [M+H]⁺.

Step 3. Ethyl (R)-1-(3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)chroman-7-yl)piperidine-4-carboxylate

A solution of ethyl (R)-1-(3-aminochroman-7-yl)piperidine-4-carboxylate (110 mg, 0.33 mmol), 3-amino-6-methylthieno[2,3-b]pyridine-2-carboxylic acid (107 mg, 0.49 mmol), Et₃N (99 mg, 0.98 mmol), and HBTU (185 mg, 0.49 mmol) in DMA (5 mL) was stirred for 2 h at room temperature. The reaction was then quenched by the addition of 5 mL of water. The resulting mixture was extracted EtOAc (3×10 mL). The combined organic layers were washed with brine (2×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel column (eluting with 1:1 EtOAc/pet. ether) afforded ethyl (R)-1-(3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)chroman-7-yl)piperidine-4-carboxylate as a yellow solid. MS: (ESI, m/z): 495 [M+H]⁺.

Step 4. (R)-1-(3-(3-Amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)chroman-7-yl)piperidine-4-carboxylic Acid

A mixture of ethyl (R)-1-(3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)chroman-7-yl)piperidine-4-carboxylate (40 mg, 0.07 mmol) and LiOH (1.6 mg, 0.07 mmol) in THF (2 mL) and water (0.5 mL) was stirred for 16 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was diluted with water (5 mL) and the pH was adjusted to 4 with aq. 3N HCl. The resulting mixture was washed with DCM (3×10 mL). Purification by prep-HPLC (Column: XBridge Shield RP18 OBD, 19×150 mm, 5 μm; Mobile phase A: Water (10 mM NH₄HCO₃), B: ACN; Gradient: 5% B to 65% B in 7 min) afforded (R)-1-(3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)chroman-7-yl)piperidine-4-carboxylic acid as a yellow solid. ¹H NMR (DMSO-d₆, 300 MHz) δ (ppm): 8.33 (d, J=8.4 Hz, 1H). 7.53 (br s, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.22 (br s, 2H), 6.91 (d, J=8.7 Hz, 1H), 6.52 (dd, J=2.4, 8.4 Hz, 1H), 6.32 (s, 1H), 4.32-4.24 (m, 1H), 4.16-4.12 (m, 1H), 3.80 (t, J=9.9 Hz, 1H), 3.57-3.52 (m, 2H), 2.86-2.82 (m, 2H), 2.73-2.65 (m, 2H), 2.58 (s, 3H), 2.50-2.28 (m, 1H), 1.91-1.84 (m, 2H), 1.69-1.57 (m, 2H). MS: (ESI, m/z): 467 [M+H]⁺.

The following examples in Table 13 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Example 6-1.

TABLE 13 LRMS Example m/z Number Structure and Compound Name [M + H]⁺ ¹H NMR 6-2¹

453 (DMSO-d₆, 300 MHz) δ(ppm): 8.32 (d, J = 8.4 Hz, 1H). 7.50 (br s, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.21 (br s, 2H), 6.87 (d, J = 8.4 Hz, 1H), 6.13 (d, J = 7.2 Hz, 1H), 5.94 (s, 1H), 4.32- 4.23 (m, 1H), 4.16-4.13 (m, 1H), 3.79 (t, J = 9.9 Hz, 1H), 3.40-3.30 (m, 2H), 3.28-3.03 (m, 3H), 2.91-2.73 (m, 2H), 2.58 (s, 3H), 2.14-2.01 (m, 2H). (R)-1-((R)-3-(3-amino-6- methylthieno[2,3-b]pyridine-2- carboxamido)chroman-7- yl)pyrrolidine-3-carboxylic acid 6-3¹

453 (DMSO-d₆, 300 MHz) δ(ppm): 8.32 (d, J = 8.4 Hz, 1H), 7.50 (br s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.21 (br s, 2H), 6.87 (d, J = 8.4 Hz, 1H), 6.12 (dd, J = 2.0, 8.4 Hz, 1H), 5.94 (s, 1H), 4.34-4.21 (m, 1H), 4.16-4.09 (m, 1H), 7.79 (t, J = 10.0 Hz, 1H), 3.37- 3.27 (m, 2H), 3.23-3.02 (m, 3H), 2.89-2.73 (m, 2H), 2.56 (s, 3H), 2.17- 2.08 (m, 2H). (S)-1-((R)-3-(3-amino-6- methylthieno[2,3-b]pyridine-2- carboxamido)chroman-7- yl)pyrrolidine-3-carboxylic acid 6-4²

438 (DMSO-d₆, 300 MHz) δ(ppm): 8.64 (s, 1H), 7.81(d, J = 7.5 Hz, 1H), 6.91- 6.85 (m, 3H), 6.21 (d, J = 7.8 Hz, 1H), 6.14 (s, 1H), 4.27-4.18 (m, 1H), 3.89-3.81 (m, 2H), 3.76-3.72 (m, 2H), 3.29-3.24 (m, 1H), 2.89-2.68 (m, 4H), 2.65 (s, 3H), 2.04-1.95 (m, 1H), 1.81- 1.70 (m, 3H). (S)-1-(6-(7-amino-3- methylthieno[2,3-b]pyrazine-6- carboxamido)-5,6,7,8- tetrahydronaphthalen-2-yl)azetidine- 3-carboxylic acid ¹Notes on procedures: In Step 1, methyl (3R)-pyrrolidine-3-carboxylate was used for Example 6-2 and methyl (3S)-pyrrolidine-3-carboxylate was used for Example 6-3. ²Notes on procedures: In Step 1, the bromide Intermediate 9 was used.

Example 7-1. (R)-3-amino-N-(7-(4-hydroxypiperidin-1-yl)chroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide

Step 1. Benzyl (R)-(7-(4-(tert-butyldimethylsilyloxy)piperidin-1-yl)chroman-3-yl)carbamate

A mixture of benzyl (R)-(7-bromochroman-3-yl)carbamate, Intermediate 2, (200 mg, 0.55 mmol), 4-(tert-butyldimethylsilyloxy)piperidine, Intermediate 39, (142 mg, 0.66 mmol), RuPhos Pd G3 (46 mg, 0.05 mmol), RuPhos (26 mg, 0.06 mmol), and Cs₂CO₃ (539 mg, 1.65 mmol) in toluene (10 mL) was stirred for 3 h at 100° C. After cooling to room temperature, the solids were filtered out and the filtrate was concentrated under vacuum. Purification by silica gel column (eluting with 1:3 EtOAc/pet. ether) afforded benzyl (R)-(7-(4-(tert-butyldimethylsilyloxy)piperidin-1-yl)chroman-3-yl)carbamate as a yellow solid. MS: (ESI, m/z): 497 [M+H]⁺.

Step 2. (R)-7-(4-(tert-butyldimethylsilyloxy)piperidin-1-yl)chroman-3-amine

A mixture of benzyl (R)-(7-(4-(tert-butyldimethylsilyloxy)piperidin-1-yl)chroman-3-yl)carbamate (170 mg, 0.34 mmol) and Pd/C (170 mg, 10%) in EtOAc (6 mL) was stirred for 2 h at room temperature under an atmosphere of hydrogen. The solids were filtered away and the filtrate was concentrated under vacuum to afford (R)-7-(4-(tert-butyldimethylsilyloxy)piperidin-1-yl)chroman-3-amine as a yellow solid. MS: (ESI, m/z): 363 [M+H]⁺.

Step 3. (R)-3-amino-N-(7-(4-(tert-butyldimethylsilyloxy)piperidin-1-yl)chroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide

A solution of (R)-7-(4-(tert-butyldimethylsilyloxy)piperidin-1-yl)chroman-3-amine (100 mg, 0.28 mmol), 3-amino-6-methylthieno[2,3-b]pyridine-2-carboxylic acid (63 mg, 0.30 mmol), Et₃N (84 mg, 0.83 mmol), and HBTU (157 mg, 0.41 mmol) in DMA (5 mL) was stirred for 30 min at room temperature. The reaction was then quenched by the addition of 10 mL of water. The resulting mixture was extracted CH₂Cl₂ (3×15 mL). The combined organic layers were washed with brine (3×15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel column (eluting with 1:1 EtOAc/pet. ether) afforded (R)-3-amino-N-(7-(4-(tert-butyldimethyl silyloxy)piperidin-1-yl)chroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide as a yellow solid. MS: (ESI, m/z): 553 [M+H]⁺.

Step 4. (R)-3-amino-N-(7-(4-hydroxypiperidin-1-yl)chroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide

A solution of (R)-3-amino-N-(7-(4-(tert-butyldimethylsilyloxy)piperidin-1-yl)chroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide (30 mg, 0.05 mmol) and HCl (4N in dioxane) (1 mL) in CH₂Cl₂ (3 mL) was stirred for 10 min at room temperature. The pH was adjusted to 8 with sat. aq. NaHCO₃. Purification by prep-HPLC (Column: XBridge Prep C18 OBD, 30×150 mm, 5 μm; Mobile phase A: Water (10 mM NH₄HCO₃), B: ACN; Flow rate: 60 mL/min; Gradient: 15% B to 50% B in 7 min) afforded (R)-3-amino-N-(7-(4-hydroxypiperidin-1-yl)chroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide as a white soild. ¹H NMR (DMSO-d₆, 300 MHz) δ (ppm): 8.32 (d, J=8.1 Hz, 1H), 7.52 (br s, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.22 (br s, 2H), 6.91 (d, J=8.4 Hz, 1H), 6.51 (dd, J=2.4, 8.4 Hz, 1H), 6.31 (s, 1H), 4.65 (br s, 1H), 4.29-4.26 (m, 1H), 4.17-4.13 (m, 1H), 3.80 (t, J=9.9 Hz, 1H), 3.64-3.58 (m, 1H), 3.48-3.44 (m, 2H), 2.87-2.73 (m, 4H), 2.59 (s, 3H), 1.80-1.76 (m, 2H), 1.48-1.43 (m, 2H). MS: (ESI, m/z): 439 [M+H]⁺.

The following examples in Table 14 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Example 7-1.

TABLE 14 LRMS Example m/z Number Structure and Compound Name [M + H]⁺ ¹H NMR 7-2¹

453 (DMSO-d₆, 400 MHz) δ(ppm): 8.33 (d, J = 8.4 Hz, 1H). 7.51 (br s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.22 (br s, 2H), 6.90 (d, J = 8.4 Hz, 1H), 6.48 (dd, J = 8.4, 2.0 Hz, 1H), 6.29 (br s, 1H), 4.39 (br s, 1H), 4.31-4.26 (m, 1H), 4.15 (dd, J = 10.0, 2.8 Hz, 1H), 3.80 (t, J = 10.0 Hz, 1H), 3.01-2.96 (m, 2H), 2.90-2.83 (m, 4H), 2.59 (s, 3H), 1.79-1.76 (m, 1H), 1.55-1.45 (m, 3-amino-N-((R)-7-(S)-3-hydroxy-3- 3H), 1.16 (s, 3H). methylpiperidin-1-yl)chroman-3-yl)- 6-methylthieno[2,3-b]pyridine-2- carboxamide 7-3¹

453 (DMSO-d₆, 400 MHz) δ(ppm): 8.33 (d, J = 8.4 Hz, 1H). 7.51 (br s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.22 (br s, 2H), 6.90 J = 8.4 Hz, 1H), 6.48 (dd, J = 8.4, 2.0 Hz, 1H), 6.29 (br s, 1H), 4.39 (br s, 1H), 4.34-4.25 (m, 1H), 4.16-4.13 (m, 1H), 3.80 (t, J = 10.0 Hz, 1H), 3.04-2.93 (m, 2H), 2.91- 2.83 (m, 4H), 2.59 (s, 3H), 1.82-1.77 (m, 1H), 1.50-1.47 (m, 3H), 1.16 (s, 3-amino-N-((R)-7-((R)-3-hydroxy-3- 3H). methylpiperidin-l-yl)chroman-3-yl)- 6-methylthieno[2,3-b]pyridine-2- carboxamide 7-4²

453 (DMSO-d₆, 300 MHz) δ(ppm): 8.63 (s, 1H), 7.77-7.74 (m, 1H), 6.94-6.84 (m, 3H), 6.71-6.49 (m, 2H), 5.14-5.07 (m, 1H), 4.14-3.95 (m, 2H), 3.66-3.58 (m, 2H), 3.42-3.16 (m, 3H), 3.00-2.70 (m, 8H), 2.63 (s, 3H), 1.98-1.89 (m, 1H), 1.80-1.67 (m, 1H). 7-amino-N-((S)-6-((R)-6-hydroxy- 1,4-diazepan-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-3- methylthieno[2,3-b]pyrazine-6- carboxamide 7-5²

453 (DMSO-d₆, 300 MHz) δ(ppm): 8.63 (s, 1H), 7.77-7.74 (m, 1H), 6.88-6.84 (m, 3H), 6.58-6.48 (m, 2H), 5.12-5.05 (m, 1H), 4.14-3.92 (m, 2H), 3.69-3.42 (m, 4H), 2.98-2.70 (m, 9H), 2.63 (s, 3H), 1.95-1.89 (m, 1H), 1.79-1.65 (m, 1H). 7-amino-N-((R)-6-((R)-6-hydroxy- 1,4-diazepan-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-3- methylthieno[2,3-b]pyrazine-6- carboxamide 7-6²

453 (DMSO-d₆, 300 MHz) δ(ppm): 8.65 (s, 1H), 7.78 (d, J = 7.8 Hz, 1H), 6.91-6.86 (m, 3H), 6.59-6.50 (m, 2H), 5.19-5.12 (m, 1H), 4.17-3.98 (m, 2H), 3.69-3.23 (m, 5H), 3.02-2.72 (m, 8H) 2.65 (s, 3H), 1.96-1.75 (m, 1H), 1.24- 1.16 (m, 1H). 7-amino-N-((S)-6-((S)-6-hydroxy- 1,4-diazepan-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-3- methylthieno[2,3-b]pyrazine-6- carboxamide 7-7²

453 (DMSO-d₆, 300 MHz) δ(ppm): 8.65 (s, 1H), 7.78 (d, J = 7.5 Hz, 1H), 6.91- 6.87 (m, 3H), 6.61-6.52 (m, 2H), 5.33-5.28 (m, 1H), 4.12-4.03 (m, 2H), 3.70-3.29 (m, 5H), 3.09-2.72 (m, 8H), 2.65 (s, 3H), 1.96-1.74 (m, 1H), 1.23- 1.16 (m, 1H). 7-amino-N-((R)-6-((S)-6-hydroxy- 1,4-diazepan-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-3- methylthieno[2,3-b]pyrazine-6- carboxamide 7-8³

452 (CD₃OD, 300 MHz) δ(ppm): 8.19 (d, J = 7.8 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 6.98 (d, J = 7.8 Hz, 1H), 6.80- 6.73 (m, 2H), 4.28-4.20 (m, 1H), 3.59-3.46 (m, 5H), 3.14-2.91 (m, 5H), 2.80-2.63 (m, 5H), 2.48-2.40 (m, 1H), 2.18-2.10 (m, 1H), 1.89-1.78 (m, 1H). 3-amino-N-((S)-6-((S)-3- (hydroxymethyl)piperazin-1-yl)- 1,2,3,4-tetrahydronaphthalen-2-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 7-9³

452 (CD₃OD, 300 MHz) δ(ppm): 8.19 (d, J = 7.8 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 6.98 (d, J = 7.8 Hz, 1H), 6.80- 6.73 (m, 2H), 4.28-4.17 (m, 1H), 3.62-3.47 (m, 4H), 3.18-3.12 (m, 1H), 3.08-2.86 (m, 5H), 2.82-2.69 (m, 2H), 2.64 (s, 3H), 2.49-2.39 (m, 1H), 2.17- 2.08 (m, 1H), 1.91-1.73 (m, 1H). 3-amino-N-((S)-6-((R)-3- (hydroxymethyl)piperazin-1-yl)- 1,2,3,4-tetrahydronaphthalen-2-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide  7-10³

452 (CD₃OD, 300 MHz) δ(ppm): 8.19 (d, J = 8.1 Hz, 1H), 7.29 (d, J = 8.1 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.80- 6.73 (m, 2H), 4.27-4.21 (m, 1H), 3.60-3.47 (m, 4H), 3.10-2.91 (m, 6H), 2.80-2.64 (m, 5H), 2.47-2.41 (m, 1H), 2.18-2.09 (m, 1H), 1.91-1.73 (m, 1H). 3-amino-N-((R)-6-((S)-3- (hydroxymethyl)piperazin-1-yl)- 1,2,3,4-tetrahydronaphthalen-2-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide  7-11³

452 (CD₃OD, 300 MHz) δ(ppm): 8.20 (d, J = 7.5 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 6.98 (d, J = 6.6 Hz, 1H), 6.80- 6.73 (m, 2H), 4.28-4.18 (m, 1H), 3.59-3.46 (m, 4H), 3.10-2.92 (m, 6H), 2.80-2.63 (m, 5H), 2.46-2.43 (m, 1H), 2.17-2.09 (m, 1H), 1.87-1.76 (m, 1H). 3-amino-N-((R)-6-((R)-3- (hydroxymethyl)piperazin-1-yl)- 1,2,3,4-tetrahydronaphthalen-2-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide ¹Notes on procedures: In Step 1, the amine Intermediate 40 was used. The Step 4 product was separated by chiral HPLC (Column: Chiralpak IC, 2 × 25 cm, 5 μm; Mobile phase A: hexanes/CH₂Cl₂ = 3:1, B: EtOH; Flow rate: 17 mL/min; Gradient: hold 50% B in 13 min) to provide Example 7-2 (RT = 9.5 min, stereochemistry assumed) and Example 7-3 (RT = 11.3 min, stereochemistry assumed). ²Notes on procedures: In Step 1, racemic bromide Intermediate 8, the amine Intermediate 45, and Pd(dppf)Cl₂—CH₂Cl₂/Xphos as the catalyst/ligand system were used. Amidation was performed with EDCI, HOBt, and DIEA in DMF. Following Step 4, the racemate was separated by chiral HPLC using the chiral column Chiralpak IA and mobile phase 90% MeOH/DCM (0.1% Et₂NH) to provide a first eluted sample which was a mixture of 2 isomers; Example 7-5 as the second eluted sample (stereochemistry assumed), and Example 7-7 as the third eluted sample (stereochemistry assumed). The mixture of 2 isomers was further separated by chiral HPLC using the chiral column Chiralpak IC and mobile phase 30% EtOH/MTBE (0.1% Et₂NH) to provide Example 7-4 as the first eluted isomer and Example 7-6 as the second eluted isomer (stereochemistry assumed). ³Notes on procedures: In Step 1, racemic bromide Intermediate 8, the amine Intermediate 46, and Pd(dppf)Cl₂—CH₂Cl₂/Xphos as the catalyst/ligand system were used. Amidation was performed with EDCI, HOBt, and DIEA in DMF. Following Step 4, the racemate was separated by chiral HPLC using the chiral column EnantioCe1-C1 and mobile phase 25% EtOH/hexanes (0.1% Et₂NH) to provide a first eluted sample 1 which was a mixture of two isomers and a second eluted sample 2 which was a mixture of two isomers. Each of the two samples were further separated by SFC using the chiral column EnantioPak A1-5 and mobile phase 50% CO₂/MeOH (0.1% iPrNH₂) to provide from sample 1, Example 7-8 as the first eluted isomer and Example 7-9 as the second eluted isomer; and from sample 2, Example 7-10 as the first eluted isomer and Example 7-11 as the second eluted isomer (stereochemistry assumed).

Example 8. (R)-3-Amino-N-(7-(4-fluoropiperidin-4-yl)chroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide

Step 1. Tert-Butyl (R)-4-(3-(((benzyloxy)carbonyl)amino)chroman-7-yl)-4-hydroxypiperidine-1-carboxylate

To a solution of benzyl (R)-(7-bromochroman-3-yl)carbamate, Intermediate 2, (500 mg, 1.35 mmol) in THF (13 mL) was added n-BuLi (2.5 M in hexane) (2.7 mL, 6.74 mmol) at −78° C. and stirring was continued for 1 h-78° C. To the reaction mixture was added a solution of tert-butyl 4-oxopiperidine-1-carboxylate (1.37 g, 6.88 mmol) in THF (2 mL) at −78° C. The resulting solution was stirred for an additional 2 h at room temperature. The reaction was quenched with sat. aq. NH₄C₁ (10 mL). The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:3 EtOAc/pet. ether) afforded tert-butyl (R)-4-(3-(((benzyloxy)carbonyl)amino)chroman-7-yl)-4-hydroxypiperidine-1-carboxylate as a yellow solid. MS: (ESI, m/z): 483 [M+H]⁺.

Step 2. Tert-Butyl (R)-4-(3-(((benzyloxy)carbonyl)amino)chroman-7-yl)-4-fluoropiperidine-1-carboxylate

To a solution of tert-butyl (R)-4-(3-(((benzyloxy)carbonyl)amino)chroman-7-yl)-4-hydroxypiperidine-1-carboxylate (180 mg, 0.36 mmol) in DCM (10 mL) was added DAST (179 mg, 1.11 mmol) at −78° C. and stirring was continued for 1 h at −78° C. The reaction was quenched with sat. aq. Na HCO₃ (15 mL). The resulting mixture was extracted with DCM (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:4 EtOAc/pet. ether) afforded tert-butyl (R)-4-(3-(((benzyloxy)carbonyl)amino)chroman-7-yl)-4-fluoropiperidine-1-carboxylate as a yellow solid. MS: (ESI, m/z): 485 [M+H]⁺.

Step 3. Tert-Butyl (R)-4-(3-aminochroman-7-yl)-4-fluoropiperidine-1-carboxylate

A mixture of tert-butyl (R)-4-(3-(((benzyloxy)carbonyl)amino)chroman-7-yl)-4-fluoropiperidine-1-carboxylate (90 mg, 0.18 mmol) and Pd/C (15 mg, 5%) in EtOAc (10 mL) was stirred for 1 h at 30° C. under an atmosphere of hydrogen. The solids were filtered away and the filtrate was concentrated under vacuum to afford tert-butyl (R)-4-(3-aminochroman-7-yl)-4-fluoropiperidine-1-carboxylate as a yellow oil. MS: (ESI, m/z): 351 [M+H]⁺.

Step 4. Tert-Butyl (R)-4-(3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)chroman-7-yl)-4-fluoropiperidine-1-carboxylate

A solution of tert-butyl (R)-4-(3-aminochroman-7-yl)-4-fluoropiperidine-1-carboxylate (65 mg, 0.15 mmol), 3-amino-6-methylthieno[2,3-b]pyridine-2-carboxylic acid (54 mg, 0.26 mmol), EDCI (54 mg, 0.28 mmol), HOBt (38 mg, 0.28 mmol), and DIEA (72 mg, 0.56 mmol) in DMF (5 mL) was stirred for 16 h at room temperature. The reaction was quenched with water (15 mL) and was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:20 MeOH/CH₂C₁₂) afforded tert-butyl (R)-4-(3-(3-amino-6-methylthieno[2,3]pyridine-2-carboxamido)chroman-7-yl)-4-fluoropiperidine-1-carboxylate as a yellow solid. MS: (ESI, m/z): 541 [M+H]⁺.

Step 5. (R)-3-Amino-N-(7-(4-fluoropiperidin-4-yl)chroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide

A solution of tert-butyl (R)-4-(3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)chroman-7-yl)-4-fluoropiperidine-1-carboxylate (35 mg, 0.06 mmol) and HCl (4 M in dioxane) (0.2 mL) in DCM (3 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by chiral HPLC (Column: Chiralpak IG, 20×250 mm, 5 μm; Mobile phase: 30% EtOH (8 mM NH₃—MeOH)/MTBE for 15 min) to afford (R)-3-amino-N-(7-(4-fluoropiperidin-4-yl)chroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide as a light yellow solid. ¹H NMR (DMSO-d₆, 300 MHz) δ (ppm): 8.33 (d, J=8.1 Hz, 1H). 7.60 (br s, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.23 (br s, 2H), 7.12 (d, J=7.8 Hz, 1H), 6.90 (dd, J=1.5, 8.1 Hz, 1H), 6.79 (s, 1H), 4.35-4.29 (m, 1H), 4.22-4.18 (m, 1H), 3.87 (t, J=9.9 Hz, 1H), 2.97-2.95 (m, 2H), 2.89-2.76 (m, 4H), 2.58 (s, 3H), 2.54-2.51 (m, 1H), 1.97-1.71 (m, 4H). MS: (ESI, m/z): 441 [M+H]⁺.

Example 9-1. N—((R)-7-(((S)-5-oxa-2-azaspiro[3.4]octan-7-yl)oxy)chroman-3-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide and Example 9-2. N—((R)-7-(((R)-5-oxa-2-azaspiro[3.4]octan-7-yl)oxy)chroman-3-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide

Step 1. Benzyl (R)-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-3-yl)carbamate

A mixture of benzyl (R)-(7-bromochroman-3-yl)carbamate, Intermediate 2, (200 mg, 0.55 mmol), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (169 mg, 0.67 mmol), Pd(dppf)Cl₂—CH₂Cl₂ (45 mg, 0.06 mmol), and KOAc (163 mg, 1.66 mmol) in dioxane (5 mL) was stirred for 3 h at 80° C. After cooling to room temperature, the resulting mixture was poured into 15 mL of water. The resulting mixture was extracted with ethyl acetate 3×15 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with gradient 1:50 to 1:5 EtOAc/pet. ether) gave benzyl (R)-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-3-yl)carbamate as a white solid. MS: (ESI, m/z): 410 [M+H]⁺.

Step 2. Benzyl (R)-(7-hydroxychroman-3-yl)carbamate

A solution of benzyl (R)-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-3-yl)carbamate (75 mg, 0.18 mmol) and hydrogen peroxide-urea adduct (43 mg, 0.46 mmol) in methanol (6 mL) was stirred for 30 min at room temperature. The solvent was removed under vacuum. The residue was diluted with 5 mL of water. The solids were collected by filtration to give benzyl (R)-(7-hydroxychroman-3-yl)carbamate as a white solid. MS: (ESI, m/z): 300 [M+H]⁺.

Step 3. Tert-Butyl 6-(((R)-3-(((benzyloxy)carbonyl)amino)chroman-7-yl)oxy)-2-azaspiro[3.4]octane-2-carboxylate

A solution of benzyl (R)-(7-hydroxychroman-3-yl)carbamate (250 mg, 0.84 mmol), tert-butyl 7-hydroxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (287 mg, 1.25 mmol), PPh₃ (328 mg, 1.25 mmol) and DIAD (253 mg, 1.25 mmol) in THF (8 mL) was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. Purification by silica gel chromatography (eluting with gradient 1:20 to 1:2 EtOAc/pet. ether) afforded tert-butyl 6-(((R)-3-(((benzyloxy)carbonyl)amino)chroman-7-yl)oxy)-2-azaspiro[3.4]octane-2-carboxylate as a white solid. MS: (ESI, m/z): 511 [M+H]⁺.

Step 4. Tert-Butyl 6-(((R)-3-aminochroman-7-yl)oxy)-2-azaspiro[3.4]octane-2-carboxylate

A mixture of tert-butyl 6-(((R)-3-(((benzyloxy)carbonyl)amino)chroman-7-yl)oxy)-2-azaspiro[3.4]octane-2-carboxylate (170 mg, 0.33 mmol) and Pd/C (80 mg, 10%) in ethyl acetate (5 mL) was stirred for 3 h at room temperature under an atmosphere of hydrogen, The solids were filtered away and the filtrate was concentrated under vacuum to give tert-butyl 6-(((R)-3-aminochroman-7-yl)oxy)-2-azaspiro[3.4]octane-2-carboxylate as light yellow oil. MS: (ESI, m/z): 377 [M+H]⁺.

Step 5. Tert-Butyl 6-(((R)-3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)chroman-7-yl)oxy)-2-azaspiro[3.4]octane-2-carboxylate

A solution of tert-butyl 6-(((R)-3-aminochroman-7-yl)oxy)-2-azaspiro[3.4]octane-2-carboxylate (110 mg, 0.29 mmol), 3-amino-6-methylthieno[2,3-b]pyridine-2-carboxylic acid (73 mg, 0.35 mmol), Et₃N (89 mg, 0.88 mmol), and HBTU (133 mg, 0.35 mmol) in DMA (3 mL) was stirred for 1 h at room temperature. Purification by reverse phase chromatography (Column: C₁₈ silica gel; Mobile phase A: water (0.1% formic acid), B: ACN; Gradient: 0% to 70% B over 20 min) afforded tert-butyl 6-(((R)-3-(3-amino-6-methylthieno[2,3]pyridine-2-carboxamido)chroman-7-yl)oxy)-2-azaspiro[3.4]octane-2-carboxylate as a yellow solid. MS: (ESI, m/z): 567 [M+H]⁺.

Step 6. N-((3R)-7-((2-azaspiro[3.4]octan-6-yl)oxy)chroman-3-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide

A solution of tert-butyl 6-((R)-3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)chroman-7-yl)oxy)-2-azaspiro[3.4]octane-2-carboxylate (75 mg, 0.13 mmol), and TFA (2 mL) in DCM (4 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum to give N-((3R)-7-((2-azaspiro[3.4]octan-6-yl)oxy)chroman-3-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide as the trifluoroacetate salt as a white solid. MS: (ESI, m/z): 467 [M+H]⁺.

Step 7. N—((R)-7-(((S)-2-azaspiro[3.4]octan-6-yl)oxy)chroman-3-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide and N—((R)-7-(((R)-2-azaspiro[3.4]octan-6-yl)oxy)chroman-3-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide

The racemic mixture of N-((3R)-7-((2-azaspiro[3.4]octan-6-yl)oxy)chroman-3-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide TFA salt (60 mg) was separated by chiral HPLC (Column: Chiralpak IG, 20×250 mm, 5 μm; Mobile phase: 20% EtOH/MTBE (0.2% IPA) for 21 min) to afford the title compounds as follows:

First eluting isomer: N—((R)-7-(((S)-2-azaspiro[3.4]octan-6-yl)oxy)chroman-3-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide as an off-white solid (RT=14.5 min, stereochemistry assumed)¹H NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.32 (d, J=8.4 Hz, 1H), 7.54 (d, J=7.6 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.21 (s, 2H), 7.00 (d, J=8.4 Hz, 1H), 6.46-6.43 (m, 1H), 6.35 (d, J=2.0 Hz, 1H), 4.99 (s, 1H), 4.31-4.16 (m, 2H), 3.98-3.95 (m, 1H), 3.86-3.81 (m, 2H), 3.74-3.42 (m, 4H), 2.94-2.84 (m, 2H), 2.58 (s, 3H), 2.42-2.17 (m, 2H). MS: (ESI, m/z): 467 [M+H]⁺.

Second eluting isomer: N—((R)-7-((R)-2-azaspiro[3.4]octan-6-yl)oxy)chroman-3-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide as an off-white solid (second eluting isomer, RT=17.4 min). ¹H NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.32 (d, J=8.4 Hz, 1H), 7.54 (d, J=7.6 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.21 (s, 2H), 7.00 (d, J=8.8 Hz, 1H), 6.46-6.43 (m, 1H), 6.34 (s, 1H), 4.99 (s, 1H), 4.29-4.16 (m, 2H), 3.99-3.95 (s, 1H), 3.88-3.81 (m, 2H), 3.68-3.42 (m, 4H), 2.94-2.88 (m, 2H), 2.67 (s, 3H), 2.43-2.31 (m, 2H). MS: (ESI, m/z): 467 [M+H]⁺.

Example 10-1. (R)-3-amino-N-(5-fluoro-7-(piperazin-1-yl)chroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide

Step 1. Tert-Butyl (R)-4-(3-(((benzyloxy)carbonyl)amino)-5-fluorochroman-7-yl)piperazine-1-carboxylate

A mixture of benzyl (R)-(7-bromo-5-fluorochroman-3-yl)carbamate, Intermediate 5-1, (500 mg, 1.32 mmol), tert-butyl piperazine-1-carboxylate (294 mg, 1.58 mmol), Pd(dppf)Cl₂—CH₂Cl₂ (106 mg, 0.13 mmol), Xphos (63 mg, 0.13 mmol), and Cs₂CO₃ (1.3 g, 3.99 mmol) in toluene (15 mL) was stirred in a sealed tube at 95° C. overnight. After cooling to room temperature, the solids were filtered out and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:3 EtOAc/pet. ether) to give tert-butyl (R)-4-(3-(((benzyloxy)carbonyl)amino)-5-fluorochroman-7-yl)piperazine-1-carboxylate as an off-white solid. MS: (ESI, m/z): 486 [M+H]⁺.

Step 2. Tert-Butyl (R)-4-(3-amino-5-fluorochroman-7-yl)piperazine-1-carboxylate

A mixture of tert-butyl (R)-4-(3-(((benzyloxy)carbonyl)amino)-5-fluorochroman-7-yl)piperazine-1-carboxylate (4.9 g, 10.10 mmol) and Pd/C (0.5 g, 10%) in EtOAc (100 mL) was stirred for 1 h at room temperature under an atmosphere of hydrogen. The solids were filtered away and the filtrate was concentrated under vacuum to afford tert-butyl (R)-4-(3-amino-5-fluorochroman-7-yl)piperazine-1-carboxylate as yellow oil. MS: (ESI, m/z): 352 [M+H]⁺.

Step 3. Tert-Butyl (R)-4-(3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-5-fluorochroman-7-yl)piperazine-1-carboxylate

A solution of tert-butyl (R)-4-(3-amino-5-fluorochroman-7-yl)piperazine-1-carboxylate (3.5 g, 9.96 mmol), 3-amino-6-methylthieno[2,3-b]pyridine-2-carboxylic acid (2.5 g, 12.01 mmol), Et₃N (3.0 g, 29.65 mmol), and HBTU (4.5 g, 11.87 mmol) in DMA (30 mL) was stirred for 30 min at room temperature. The reaction was quenched by the addition of 60 mL of water. The resulting mixture was extracted with CH₂Cl₂ (50 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by reverse phase chromatography (Column: C₁₈ silica gel; Mobile phase A: water (10 mM NH₄HCO₃), B: ACN; Gradient: 0% to 100% B over 30 min; Flow rate: 90 mL/min) afforded tert-butyl (R)-4-(3-(3-amino-6-methylthieno[2,3]pyridine-2-carboxamido)-5-fluorochroman-7-yl)piperazine-1-carboxylate as an off-white solid. MS: (ESI, m/z): 542 [M+H]⁺.

Step 4. (R)-3-Amino-N-(5-fluoro-7-(piperazin-1-yl)chroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide

A solution of tert-butyl (R)-4-(3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-5-fluorochroman-7-yl)piperazine-1-carboxylate (30 mg, 0.05 mmol) and TFA (1 mL) in CH₂Cl₂ (2 mL) was stirred for 30 min at room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by prep-HPLC (Column: XBridge Prep C18 OBD, 19×50 mm, 5 μm; Mobile phase A: water (10 mM NH₄HCO₃), B: ACN; Gradient: 25% B to 75% B in 7 min) to afford (R)-3-amino-N-(5-fluoro-7-(piperazin-1-yl)chroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide as a yellow solid. ¹H NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.33 (d, J=9 MHz, 1H), 7.58 (d, J=9 MHz, 1H), 7.31 (d, J=6 MHz, 1H), 7.22 (s, 2H), 6.43-6.40 (m, 1H), 6.17 (s, 1H), 4.40-4.20 (m, 1H), 4.19-4.12 (m, 1H), 3.89-3.82 (m, 1H), 3.32 (s, 1H), 3.01-2.97 (m, 4H), 2.80-2.74 (m, 6H), 2.58 (s, 3H). MS: (ESI, m/z): 442 [M+H]⁺.

The following examples in Table 15 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Example 10-1.

TABLE 15 LRMS Example m/z Number Structure and Compound Name [M + H]⁺ ¹H NMR 10-2¹

472 (DMSO-d₆, 400 MHz) δ(ppm): 8.33 (d, J = 8.4 Hz, 1H), 7.56 (br s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.23 (br s, 2H), 5.95 (d, J = 12.4 Hz, 1H), 5.77 (s, 1H), 4.27 (s, 1H), 4.16-4.14 (m, 1H), 3.84-3.79 (m, 1H), 3.63-3.621 (m, 1H), 3.53-3.40 (m, 2H), 3.38- 3.33 (m, 1H), 3.29 (s, 3H), 3.13-3.11 (m, 1H), 2.92-2.80 (m, 2H), 2.74-2.72 (m, 1H), 2.58 (s, 3H), 1.95 (br s, 2H). 3-amino-N-((R)-7-((3R,4R)-3-amino- 4-methoxypyrrolidin-1-yl)-5- fluorochroman-3-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 10-3¹

472 (DMSO-d₆, 400 MHz) δ(ppm): 8.33 (d, J = 8.4 Hz, 1H), 7.56 (br s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.23 (br s, 2H), 5.96 (d, J = 12.4 Hz, 1H), 5.78 (s, 1H), 4.27 (s, 1H), 4.16-4.14 (m, 1H), 3.84-3.79 (m, 1H), 3.63-3.621 (m, 1H), 3.53-3.40 (m, 2H), 3.38- 3.33 (m, 1H), 3.29 (s, 3H), 3.13-3.11 (m, 1H), 2.92-2.80 (m, 2H), 2.74-2.72 (m, 1H), 2.58 (s, 3H), 1.95 (br s, 2H). 3-amino-N-((R)-7-((3R,4R)-3-amino- 4-methoxypyrrolidin-1-yl)-5- fluorochroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide 10-4²

450 (DMSO-d₆, 400 MHz) δ(ppm): 8.32 (d, J = 8.0 Hz, 1H), 7.58 (br s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.22 (br s, 2H), 6.38 (d, J = 12.4 Hz, 1H), 6.16 (s, 1H), 4.32-4.15 (m, 2H), 3.87-3.78 (m, 1H), 2.89-2.67 (m, 2H), 2.58 (s, 3H). (R)-3-amino-N-(5-fluoro-7- (piperazin-l-yl-2,2,3,3,5,5,6,6- d8)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide   10-5^(2,3)

442 (DMSO-d₆, 400 MHz) δ(ppm): 8.33 (d, J = 9 MHz, 1H), 7.58 (d, J = 9 MHz, 1H), 7.31 (d, J = 6 MHz, 1H), 7.22 (s, 2H), 6.43-6.40 (m, 1H), 6.17 (s, 1H), 4.40-4.20 (m, 1h), 4.19-4.12 (m, 1H), 3.89-3.82 (m, 1H), 3.32 (s, 1H), 3.01-2.97 (m, 4H), 2.80-2.74 (m, 6H), 2.58 (s, 3H). (S)-3-amino-N-(5-fluoro-7- (piperazin-1-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 10-6²

484 (DMSO-d₆, 400 MHz) δ(ppm): 8.33 (d, J = 8.4 Hz, 1H). 7.58 (br s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.23 (br s, 2H), 6.46 (dd, J = 2.0, 12.8 Hz, 1H), 6.24 (s, 1H), 4.32-4.27 (m, 1H), 4.20- 4.15 (m, 1H), 3.86 (t, J = 10.0 Hz, 1H), 3.79-3.77 (m, 2H), 3.68-3.65 (m, 2H), 3.12-3.00 (m, 6H), 2.91-2.67 (m, 2H), 2.58 (s, 3H), 2.01 (br s, 1H). N-((3R)-7-(9-oxa-3,7- diazabicyclo[3.3.1]nonan-3-yl)-5- fluorochroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2- carboxamide    10-7^(2,4,5)

468 (CD₃OD, 400 MHz) δ(ppm): 7.05 (s, 1H), 6.15 (d, J = 12.6 Hz, 1H), 6.06 (s, 1H), 4.48-4.37 (m, 1H), 4.28-4.23 (m, 1H), 3.96-3.93 (m, 1H), 3.85-3.83 (m, 2H), 3.52-3.48 (m, 4H), 3.12-2.93 (m, 1H), 2.79 (s, 3H), 2.77-2.55 (m, 2H), 1.67-1.64 (m, 1H). N-((3R)-7-(3,6- diazabicyclo[3.1.1]heptan-3-yl)-5- fluorochroman-3-yl)-3-amino-4,6- dimethylthieno[2,3-b]pyridine-2-carboxamide   10-8^(2,5)

455 (DMSO-d₆, 400 MHz) δ(ppm): 8.65 (s, 1H), 7.80 (d, J = 7.2 Hz, 1H), 6.97 (br s, 2H), 6.14 (dd, J = 2.0, 12.8 Hz, 1H), 5.97 (s, 1H), 4.35-3.26 (m, 1H), 4.20-4.17 (m, 1H), 3.87 (t, J = 9.6 Hz, 1H), 3.67-3.66 (m, 2H), 3.41-3.31 (m, 4H), 2.92-2.86 (m, 1H), 2.79-2.68 (m, 1H), 2.66 (s, 3H), 2.50-2.49 (m, 1H), 1.46-1.45 (m, 1H). N-((3R)-7-(3,6- diazabicyclo[3.1.1]heptan-3-yl)-5- fluorochroman-3-yl)-7-amino-3- methylthieno[2,3-b]pyrazine-6-carboxamide   10-9^(4,5)

456 (CD₃OD, 400 MHz) δ(ppm): 7.04 (s, 1H), 6.34 (dd, J = 2.4, 12.4 Hz, 1H), 6.25 (s, 1H), 4.45-4.4.40 (m, 1H), 4.32-4.10 (m, 1H), 3.94-3.90 (m, 1H), 3.14-3.11 (m, 4H), 3.01-2.95 (m, 5H), 2.78 (s, 3H), 2.76-2.74 (m, 1H), 2.50 (s, 3H). (R)-3-amino-N-(5-fluoro-7- (piperazin-1-yl)chroman-3-yl)-4,6- dimethylthieno[2,3-b]pyridine-2- carboxamide  10-10⁵

443 (DMSO-d₆, 400 MHz) δ(ppm): 8.66 (s, 1H), 7.85 (d, J = 7.2 Hz, 1H), 6.70 (br s, 2H), 6.38 (dd, J = 2.4, 12.8 Hz, 1H), 6.17 (s, 1H), 4.34-4.25 (m, 2H), 4.19-4.16 (m, 1H), 3.89-3.84 (m, 1H), 3.00-2.98 (m, 4H), 2.91-2.85 (m, 6H), 2.79 (s, 3H). (R)-7-amino-N-(5-fluoro-7- (piperazin-1-yl)chroman-3-yl)-3- methylthieno[2,3-b]pyrazine-6- carboxamide  10-11⁶

458 (DMSO-d₆, 300 MHz) δ(ppm): 8.32 (d, J = 8.7 Hz, 1H). 7.46 (br s, 1H), 7.21 (br s, 2H), 6.68 (d, J = 9.0 Hz, 1H), 6.37 (dd, J = 2.1, 12.9 Hz, 1H), 6.17 (s, 1H), 4.30-4.21 (m, 1H), 4.19- 4.16 (m, 1H), 3.93 (s, 3H), 3.83 (t, J = 9.9 Hz, 1H), 3.02-2.98 (m, 4H), 2.90- 2.68 (m, 6H). (R)-3-amino-N-(5-fluoro-7- (piperazin-1-yl)chroman-3-yl)-6- methoxythieno[2,3-b]pyridine-2- carboxamide  10-12²

485 (DMSO-d₆, 300 MHz) δ(ppm): 8.67 (s, 1H), 7.85 (br s, 1H), 7.00 (br s, 2H), 6.46 (dd, J = 2.1, 12.9 Hz, 1H), 6.23 (s, 1H), 4.34-4.28 (m, 1H), 4.28- 4.15 (m, 1H), 3.91-3.85 (m, 1H), 3.74-3.65 (m, 4H), 3.10-2.70 (m, 9H), 2.70-2.55 (s, 3H). N-((3R)-7-(9-oxa-3,7- diazabicyclo[3.3.1]nonan-3-yl)-5- fluorochroman-3-yl)-7-amino-3- methylthieno[2,3-b]pyrazine-6-carboxamide    10-13^(2,4)

498 (DMSO-d₆, 400 MHz) δ(ppm): 7.62 (br s, 1H). 7.04 (s, 1H), 6.87 (br s, 2H), 6.45 (dd, J = 2.0, 12.8 Hz, 1H), 6.23 (s, 1H), 4.30-4.25 (m, 1H), 4.19- 4.16 (m, 1H), 3.86 (t, J = 10.0 Hz, 1H), 3.74-3.72 (m, 2H), 3.68-3.65 (m, 2H), 3.13-2.95 (m, 6H), 2.90-2.85 (m, 1H), 2.79-2.66 (m, 1H), 2.62 (s, 3H), 2.53 (s, 3H). N-((3R)-7-(9-oxa-3,7- diazabicyclo[3.3.1]nonan-3-yl)-5- fluorochroman-3-yl)-3-amino-4,6- dimethylthieno[2,3-b]pyridine-2- carboxamide    10-14^(5,7)

510 (DMSO-d₆, 300 MHz) δ(ppm): 7.97 (d, J = 6.9 Hz, 1H), 7.54 (br s, 1H), 6.68 (br s, 2H), 6.38 (d, J = 11.1 Hz, 1H), 6.21 (s, 1H), 4.32-4.16 (m, 2H), 3.90-3.84 (m, 1H), 3.09-2.70 (m, 10H), 2.50 (s, 3H), 2.30-2.27 (m, 1H). (R)-3-amino-N-(5-fluoro-7- (piperazin-1-yl)chroman-3-yl)-6- methyl-4-(trifluoromethyl)thieno[2,3- b]pyridine-2-carboxamide     10-15^(2,5,8)

456 (DMSO-d₆, 400 MHz) δ(ppm): 8.31 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 6.60 (br s, 2H), 6.40-6.37 (m, 1H), 6.17 (s, 1H), 4.57-4.53 (m, 1H), 4.29-4.27 (m, 1H), 4.18-4.13 (m, 1H), 3.05 (s, 3H), 3.00-2.98 (m, 4H), 2.95-2.88 (m, 2H), 2.85-2.84 (m, 4H), 2.57 (s, 3H). 3-amino-N-[(3R)-5-fluoro-7- (piperazin-1-yl)-3,4-dihydro-2H-1- benzopyran-3-yl)-N,6- dimethylthieno[2,3-b]pyridine-2- carboxamide       10-16^(2,3,5,8)

456 (DMSO-d₆, 400 MHz) δ(ppm): 8.31 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 6.60 (br s, 2H), 6.41-6.37 (m, 1H), 6.17 (s, 1H), 4.57-4.55 (m, 1H), 4.30-4.27 (m, 1H), 4.18-4.13 (m, 1H), 3.05 (s, 3H), 3.00-2.84 (m, 7H), 2.79-2.77 (m, 4H), 2.57 (s, 3H). 3-amino-N-[(3S)-5-fluoro-7- (piperazin-1-yl)-3,4-dihydro-2H-1- benzopyran-3-yl]-N,6- dimethylthieno[2,3-b]pyridine-2- carboxamide ¹Notes on procedures: In Step 1, the amine Intermediate 35 was used; RuPhos Pd G3/RuPhos was used as the catalyst/ligand system. After Step 4, the racemic mixture of 3-amino-N-((3R)-7-(3-amino-4-methoxypyrrolidin-1-yl)-5-fluorochroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide was separated by chiral HPLC (Column: Chiralpak IC, 2 × 25 cm, 5 μm; Mobile phase A: MTBE (0.1% Et₂NH), B: EtOH; Gradient: hold 20% B in 18 min) to provide Example 10-2 (RT = 8.2 min, stereochemistry assumed) and Example 10-3 (RT = 10.3 min, stereochemistry assumed). ²Notes on procedures: In Step 1, RuPhos Pd G3/RuPhos was used as the catalyst/ligand system. ³Notes on procedures: In Step 1, benzyl (S)-(7-bromo-5-fluorochroman-3-yl)carbamate was used. ⁴Notes on procedures: In Step 3, the carboxylic acid Intermediate 21 was used. ⁵Notes on procedures: In Step 4, the crude product was treated with NH₃ in MeOH to afford the free base before purification by prep-HPLC. ⁶Notes on procedures: In Step 3, the carboxylic acid Intermediate 19 was used. ⁷Notes on procedures: In Step 3, the carboxylic acid Intermediate 22 was used. ⁸Notes on procedures: Before the Cbz-deprotection (Step 2), the carbamate was methylated by treatment with NaH (2 eq.) and MeI (1.5 eq.) in DMF at 25° C. The reaction was quenched with water and an extractive workup with EtOAc was performed, followed by purification by silica gel chromatography, to afford the corresponding tert-butyl 4-(3-[[(benzyloxy)carbonyl](methyl)amino]-5-fluoro-3,4-dihydro-2H-1-benzopyran-7-yl)piperazine-1-carboxylate. MS (ESI, m/z): 500 [M + H]⁺.

Example 11-1. N-((2S)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide and Example 11-2. N-((2R)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide

Step 1. Tert-Butyl 3-(6-(((benzyloxy)carbonyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

A mixture of benzyl (6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate, Intermediate 8, (2 g, 5.55 mmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.171 g, 5.52 mmol), Pd(dppf)Cl₂ (404.96 mg, 0.55 mmol), Xphos (527 mg, 1.11 mmol), Cs₂CO₃ (5.3 g, 16.28 mmol) in toluene (40 mL) was stirred overnight at 100° C. After cooling to room temperature, the reaction mixture was concentrated under vacuum. Purification by silica gel chromatography (eluting with gradient 1:100 to 2:5 EtOAc/pet. ether) afforded tert-butyl 3-(6-(((benzyloxy)carbonyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. MS: (ESI, m/z): 492 [M+H]⁺.

Step 2. Tert-Butyl 3-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

A mixture of tert-butyl 3-(6-(((benzyloxy)carbonyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.4 g, 2.85 mmol) and Pd/C (1.4 g, 13.16 mmol) in ethanol (30 mL) was stirred for 1 h at room temperature under an atmosphere of hydrogen. The solids were filtered away and the filtrate was concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:10 MeOH/CH₂C₁₂) afforded tert-butyl 3-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. MS: (ESI, m/z): 358 [M+H]⁺.

Step 3. Tert-Butyl 3-(6-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

A mixture of 3-amino-6-methylthieno[2,3-b]pyridine-2-carboxylic acid (175 mg, 0.84 mmol), tert-butyl 3-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.84 mmol), EDCI (193 mg, 1.01 mmol), HOBt (136 mg, 1.01 mmol), DIEA (325 mg, 2.52 mmol) in DMF (20 mL) was stirred for 18 h at 20° C. The reaction mixture was diluted with water (50 mL) and was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:3 EtOAc/pet. ether) afforded tert-butyl 3-(6-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. MS: (ESI, m/z): 548 [M+H]⁺.

Step 4. Tert-Butyl 3-((S)-6-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and tert-Butyl 3-((R)-6-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

The racemic mixture of tert-butyl 3-(6-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate was separated by chiral HPLC (Column: (R,R)-WHELK-O1-Kromasil, 0.5×25 cm, 5 μm; Mobile phase: MeOH; Detector: UV 190 to 500 nm) to afford the title compounds as follows: tert-butyl 3-((S)-6-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a white solid (first eluting isomer, RT=15.5 min) and tert-butyl 3-((R)-6-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a white solid (second eluting isomer, RT=20.4 min).

Step 5. N-((2S)-6-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide

A solution of tert-butyl 3-((S)-6-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70 mg, 0.13 mmol) and TFA (7 mL) in DCM (28 mL) was stirred for 1 h at room temperature. The reaction mixture was concentrated under vacuum. The resulting solution was diluted with 5 mL of DCM. The pH value of the solution was adjusted to 8 with NH₃ (solution in MeOH). The resulting mixture was concentrated under vacuum. Purification by prep-HPLC (Column: XBridge BEH C18 OBD, 130 Å, 19×150 mm, 5 μm; Mobile phase A: water (10 mM NH₄HCO₃), B: ACN; Gradient: 5% B to 52% B over 8 min) afforded N-((2S)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide as an off-white solid. ¹H NMR (CD₃OD, 400 MHz) δ (ppm): 8.19 (d, J=8.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 6.65 (d, J=8.4 Hz, 1H), 6.58 (s, 1H), 4.24-4.23 (m, 1H), 3.63-3.60 (m, 2H), 3.45-3.41 (m, 2H), 3.02-2.68 (m, 6H), 2.64 (s, 3H), 2.14-2.08 (m, 1H), 1.92-1.75 (m, 5H). MS: (ESI, m/z): 449 [M+H]⁺.

Step 6. N-((2R)-6-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide

A solution of tert-butyl 3-((R)-6-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70 mg, 0.13 mmol) and TFA (7 mL) in DCM (28 mL) was stirred for 1 h at room temperature. The reaction mixture was concentrated under vacuum. The resulting solution was diluted with 5 mL of DCM. The pH value of the solution was adjusted to 8 with NH₃ (7M in MeOH). The resulting mixture was concentrated under vacuum. Purification by prep-HPLC (Column: XBridge BEH C18 OBD, 130 Å, 19×150 mm, 5 μm; Mobile phase A: water (10 mM NH₄HCO₃), B: ACN; Gradient: 5% B to 52% B over 8 min) afforded N-((2R)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide as an off-white solid. ¹H NMR (CD₃OD, 400 MHz) δ (ppm): 8.20 (d, J=8.4 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 6.66 (d, J=8.4 Hz, 1H), 6.59 (s, 1H), 4.26-4.17 (m, 1H), 3.65-3.61 (m, 2H), 3.45-3.39 (m, 3H), 3.00-2.71 (m, 6H), 2.64 (s, 3H), 2.12-2.09 (m, 1H), 1.91-1.75 (m, 5H). MS: (ESI, m/z): 449 [M+H]⁺.

Example 11-1. N-((2S)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide

Method 2.

N-((2S)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide can also be prepared according to Method 1, starting from benzyl (S)-(6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate, Intermediate 9, and skipping the Step 4 chiral separation.

Example 11-2. N-((2R)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide

Method 2.

N-((2R)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide can also be prepared according to Method 1, starting from benzyl (R)-(6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate, Intermediate 10, and skipping the Step 4 chiral separation.

The following examples in Table 16 were prepared using standard chemical manipulations and procedures similar to Method 1 (or Method 2 where indicated) for the preparation of Examples 11-1 and 11-2.

TABLE 16 LRMS Example m/z Number Structure and Compound Name [M + H]⁺ ¹H NMR 11-3¹ 

466 (CD₃OD, 300 MHz) δ(ppm): 8.04 (d, J = 9.9 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.73-6.57 (m, 2H), 4.23 (m, 1H), 3.70 (s, 2H), 3.47 (m, 2H), 3.06- 2.67 (m, 6H), 2.61 (m, 3H), 2.17- 2.01 (m, 1H), 1.88 (m, 5H). N-((2S)-6-(3,8- diazabicyclo[3.2.1]octan-3-yl)- 1,2,3,4-tetrahydronaphthalen-2-yl)-3- amino-5-fluoro-6-methylthieno[2,3- b]pyridine-2-carboxamide 11-4¹ 

466 (CD₃OD, 300 MHz) δ(ppm): 8.04 (d, J = 9.9 Hz, 1H), 6.94 (d, J = 8.5 Hz, 1H), 6.73-6.56 (m, 1H), 4.32-4.15 (m, 1H), 3.68 (m,, 1H), 3.52-3.40 (m, 2H), 3.05-2.67 (m, 6H), 2.61 (m, 3H), 2.11 (m, 1H), 1.98-.74 (m, 5H). N-((2R)-6-(3,8- diazabicyclo[3.2.1]octan-3-yl)- 1,2,3,4-tetrahydronaphthalen-2-yl)-3- amino-5-fluoro-6-methylthieno[2,3- b]pyridine-2-carboxamide 11-5² 

464 (DMSO-d₆, 400 MHz) δ(ppm): 8.30 (d, J = 8.7 Hz, 1H), 7.40 (d, J = 7.5 Hz, 1H), 7.12 (s, 1H), 6.89-6.85 (m, 2H), 6.61-6.57 (m, 1H), 6.50 (s, 1H), 4.12- 4.02 (m, 1H), 3.93 (s, 3H), 3.50 (s, 2H), 3.31 (s, 2H), 2.80-2.66 (m, 6H), 2.51-2.49 m, 1H), 1.99-1.92 (m, 1H), 1.77-1.65 (m, 5H). N-((2S)-6-(3,8- diazabicyclo[3.2.1]octan-3-yl)- 1,2,3,4-tetrahydronaphthalen-2-yl)-3- amino-6-methoxythieno[2,3- b]pyridine-2-carboxamide 11-6² 

464 (DMSO-d₆, 400 MHz) δ(ppm): 8.30 (d, J = 8.7 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.12 (s, 1H), 6.88-6.85 (m, 2H), 6.61-6.57 (m, 1H), 6.51 (s, 1H), 4.11- 4.02 (m, 1H), 3.93 (s, 3H), 3.51 (s, 2H), 3.31 (s, 2H), 2.80-2.67 (m, 6H), 2.51-2.49 (m, 1H), 1.97-1.94 (m, 1H), 1.77-1.68 (m, 5H). ((2R)-6-(3,8- diazabicyclo[3.2.1]octan-3-yl)- 1,2,3,4-tetrahydronaphthalen-2-yl)-3- amino-6-methoxythieno[2,3- b]pyridine-2-carboxamide 11-7³ 

449 (CD₃OD, 400 MHz) δ(ppm): 8.57 (s, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.65- 6.68 (m, 1H), 6.61 (s, 1H), 4.22-4.24 (m, 1H), 3.71 (s, 2H), 3.47 (d, J = 15.1 Hz, 2H), 2.83-3.04 (m, 5H), 2.68 (s, 4H), 2.10 (s, 1H), 1.85-1.88 (m, 5H). N-((2S)-6-(3,8- diazabicyclo[3.2.1]octan-3-yl)- 1,2,3,4-tetrahydronaphthalen-2-yl)-7- amino-3-methylthieno[2,3- b]pyrazine-6-carboxamide 11-8³ 

449 (CD₃OD, 400 MHz) δ(ppm): 8.57 (s, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.65- 6.68 (m, 1H), 6.60 (d, J = 2.5 Hz, 1H), 4.25 (s, 1H), 3.72 (s, 2H), 3.46 (d, J = 4.9 Hz, 2H), 2.83-3.04 (m, 5H), 2.68 (s, 4H), 2.10 (s, 1H), 1.76- 1.94 (m, 5H). N-((2R)-6-(3,8- diazabicyclo[3.2.1]octan-3-yl)- 1,2,3,4-tetrahydronaphthalen-2-yl)-7- amino-3-methylthieno[2,3- b]pyrazine-6-carboxamide 11-9⁴ 

430 (CD₃OD, 400 MHz) δ(ppm): 8.75 (d, J = 2.0 Hz, 1H), 8.57-8.42 (m, 1H), 7.53 (d, J = 3.6 Hz, 1H),7.06-6.87 (m, 1H), 6.72-6.56 (m, 3H), 4.45- 4.21 (m, 3H), 3.61 (s, 2H), 3.56-3.37 (m, 2H), 3.13-2.69 (m, 6H), 2.23- 2.12 (m, 1H), 1.94-1.76 (m, 5H), 1.56-1.27 (m, 3H). N-((2S)-6-(3,8- diazabicyclo[3.2.1]octan-3-yl)- 1,2,3,4-tetrahydronaphthalen-2-yl)-1- ethyl-1H-pyrrolo[2,3-b]pyridine-5- carboxamide 11-10⁴

430 (CD₃OD, 400 MHz) δ(ppm): 8.74 (d, J = 2.1 Hz, 1H), 8.51-8.42 (m, 1H), 7.52 (d, J = 3.6 Hz, 1H), 7.08-6.79 (m, 1H), 6.67 (m, 1H), 6.65-6.47 (m, 2H), 4.42-4.22 (m, 3H), 3.67 (s, 2H), 3.50-3.41 (m, 2H), 3.10-2.71 (m, 6H), 2.21-2.12 (m, 1H), 1.95- 1.76 (m, 5H), 1.52-1.37 (m, 3H). N-((2R)-6-(3,8- diazabicyclo[3.2.1]octan-3-yl)- 1,2,3,4-tetrahydronaphthalen-2-yl)-1- ethyl-1H-pyrrolo[2,3- b]pyridine-5-carboxamide 11-11⁵

440 (DMSO-d₆, 400 MHz) δ(ppm): 8.30 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H),7.15 (s, 2H), 6.57-6.49 (m, 2H), 4.13-4.07 (m, 1H),3.01-2.99 (m, 4H), 2.92-2.78 (m, 7H), 2.59-2.56 (m, 4H), 1.97-1.94 (m, 1H), 1.78-1.68 (m, 1H). (S)-3-amino-N-(8-fluoro-6- (piperazin-l-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 11-12⁵

440 (DMSO-d₆, 400 MHz) δ(ppm): 8.31 (d, J = 8.1 Hz, 1H), 7.61(d, J = 7.8 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.17 (s, 2H), 6.57-6.49 (m, 2H), 4.15-4.06 (m, 1H), 3.01-2.98 (m, 4H), 2.93-2.80 (m, 7H), 2.58-2.54 (m, 4H), 1.97-1.94 (m, 1H), 1.78-1.68 (m, 1H). (R)-3-amino-N-(8-fluoro-6- (piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 11-13⁶

467 (DMSO-d₆, 300 MHz) δ(ppm): 8.65 (s, 1H), 7.85 (d, J = 7.8 Hz, 1H), 6.93 (s, 2H), 6.37-6.45 (m, 2H), 4.10-4.15 (m, 1H), 3.47-3.51 (m, 2H), 3.35- 3.38 (m, 2H), 2.65-2.95 (m, 6H), 2.64 (s, 3H), 2.54-2.60 (m, 1H), 1.93-2.00 (m, 1H), 1.71-1.80 (m, 1H), 1.62-1.70 (m, 4H). N-((2S)-6-(3,8- diazabicyclo[3.2.1]octan-3-yl)-8- fluoro-1,2,3,4-tetrahydronaphthalen- 2-yl)-7-amino-3-methylthieno[2,3- b]pyrazine-6-carboxamide 11-14⁶

467 (DMSO-d₆, 300 MHz) δ(ppm): 8.65 (s, 1H), 7.85 (d, J = 7.8 Hz, 1H), 6.93 (s, 2H), 6.37-6.45 (m, 2H), 4.10-4.15 (m, 1H), 3.47-3.51 (m, 2H), 3.35- 3.38 (m, 2H), 2.65-2.95 (m, 6H), 2.64 (s, 3H), 2.54-2.60 (m, 1H), 1.93-2.00 (m, 1H), 1.71-1.80 (m, 1H), 1.62-1.70 (m, 4H). N-((2R)-6-(3,8- diazabicyclo[3.2.1]octan-3-yl)-8- fluoro-1,2,3,4-tetrahydronaphthalen- 2-yl)-7-amino-3-methylthieno[2,3- b]pyrazine-6-carboxamide 11-15⁷

438 (CD₃OD, 300 MHz) δ(ppm): 8.22 (d, J = 12.0 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 9 Hz, 1H), 6.63 (dd, J = 2.4, 8.4 Hz, 1H), 6.44 (s, 1H), 4.58- 4.53 (m, 1H), 4.26-4.13 (m, 2H), 3.31-3.23 (m, 1H), 3.16-3.08 (m, 4H), 3.02-2.65 (m, 4H), 2.65 (s, 3H), 1.37 (d, J = 6.9 Hz, 3H). 3-amino-6-methyl-N-((3R,4R)-4- methyl-7-(piperazin-1-yl)chroman-3- yl)thieno[2,3-b]pyridine-2- carboxamide 11-16⁷

438 (CD₃OD, 300 MHz) δ(ppm): 8.22 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.13 (d, J = 8.7 Hz, 1H), 6.62 (dd, J = 2.4, 8.4 Hz, 1H), 6.42 (s, 1H), 4.24-4.20 (m, 1H), 4.16-4.10 (m, 1H), 4.00-3.94 (m, 1H), 3.13-3.08 (m, 4H), 3.02-2.94 (m, 5H), 2.65 (s, 3H), 1.37 (d, J = 6.9 Hz, 3H) 3-amino-6-methyl-N-((3R,4S)-4- methyl-7-(piperazin-1-yl)chroman-3- yl)thieno[2,3-b]pyridine-2- carboxamide 11-17⁷

438 (CD₃OD, 300 MHz) δ(ppm): 8.22 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.13 (d, J = 9.0 Hz, 1H), 6.63 (dd, J = 2.4, 8.4 Hz, 1H), 6.42 (s, 1H), 4.24-4.20 (m, 1H), 4.16-4.10 (m, 1H), 4.00-3.94 (m, 1H), 3.13-3.08 (m, 4H), 3.02-2.94 (m, 4H), 2.65 (s, 3H), 1.37 (d, J = 6.9 Hz, 3H). 3-amino-6-methyl-N-((3S,4R)-4- methyl-7-(piperazin-1-yl)chroman-3- yl)thieno[2,3-b]pyridine-2- carboxamide 11-18⁷

438 (CD₃OD, 300 MHz) δ(ppm): 8.22 (d, J = 12.0 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 9 Hz, 1H), 6.63 (dd, J = 2.4, 8.4 Hz, 1H), 6.44 (s, 1H), 4.58- 4.53 (m, 1H), 4.26-4.13 (m, 2H), 3.31-3.23 (m, 1H), 3.16-3.08 (m, 4H), 3.02-2.65 (m, 4H), 2.65 (s, 3H), 1.37 (d, J = 6.9 Hz, 3H). 3-amino-6-methyl-N-((3S,4S)-4- methyl-7-(piperazin-1-yl)chroman-3- yl)thieno[2,3-b]pyridine-2- carboxamide 11-19⁸

423 (CD₃OD, 400 MHz) δ(ppm): 8.56 (s, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.79- 6.72 (m, 2H), 4.27-4.23 (m, 1H), 3.13-2.74 (m, 12H), 2.67 (s, 3H), 2.14-2.10 (m, 1H), 1.86-1.76 (m, 1H). (S)-7-amino-3-methyl-N-(6- (piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)thieno[2,3- b]pyrazine-6-carboxamide 11-20⁸

423 (CD₃OD, 400 MHz) δ(ppm): 8.57 (s, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.80- 6.73 (m, 2H), 4.28-4.23 (m, 1H), 3.13-2.74 (m, 12H), 2.68 (s, 3H), 2.14-2.11 (m, 1H), 1.87-1.75 (m, 1H). (R)-7-amino-3-methyl-N-(6- (piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)thieno[2,3- b]pyrazine-6-carboxamide 11-21⁹

422 (DMSO-d₆, 400 MHz) δ(ppm): 8.29 (s, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.15 (s, 2H), 6.91 (d, J = 8.4 Hz, 1H), 6.72-6.70 (m, 1H), 6.62 (s, 1H), 4.13-4.09 (m, 1H), 2.98- 2.96 (m, 4H), 2.87-2.67 (m, 8H), 2.58 (s, 3H), 1.98-1.95 (m, 1H), 1.79-1.71 (m, 1H). (S)-3-amino-6-methyl-N-(6- (piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)thieno[2,3- b]pyridine-2-carboxamide 11-22⁹

422 (DMSO-d₆, 400 MHz) δ(ppm): 8.30 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.15 (s, 2H), 6.91 (d, J = 8.4 Hz, 1H), 6.72-6.69 (m, 1H), 6.62 (s, 1H), 4.13- 4.07 (m, 1H), 2.98-2.96 (m, 4H), 2.83-2.74 (m, 8H), 2.58 (s, 3H), 1.98- 1.95 (m, 1H), 1.79-1.71 (m, 1H). (R)-3-amino-6-methyl-N-(6- (piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)thieno[2,3- b]pyridine-2-carboxamide 11-23¹⁰

431 (CD₃OD, 400 MHz) δ(ppm): 8.51 (s, 1H), 8.51 (s, 1H), 7.90 (d, J = 3.6 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 6.75- 6.67 (m, 2H), 6.61 (s, 1H), 4.59-4.54 (m, 2H), 4.41-4.36 (m, 1H), 3.62 (s, 2H), 3.46-3.43 (m, 2H), 3.13-3.07 (m, 1H), 2.95-2.80 (m, 5H), 2.19-2.16 (m, N-((2R)-6-(3,8- 1H), 2.00-1.84 (m, 5H), 1.56-1.53 (m, diazabicyclo[3.2.1]octan-3-yl)- 3H). 1,2,3,4-tetrahydronaphthalen-2-yl)-7- ethyl-7H-pyrrolo[2,3-c]pyridazine-3- carboxamide  11-24¹⁰

431 (CD₃OD, 400 MHz) δ(ppm): 8.51 (s, 1H), 7.90 (d, J = 3.2 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.75-6.61 (m, 3H), 4.59-4.54 (m, 2H), 4.41-4.39 (m, 1H), 3.62 (s, 2H), 3.46-3.43 (m, 2H), 3.12- 3.07 (m, 1H), 2.96-2.80 (m, 5H), 2.19-2.17 (m, 1H), 1.99-1.84 (m, 5H), N-((2S)-6-(3,8- 1.56-1.53 (m, 3H). diazabicyclo[3.2.1]octan-3-yl)- 1,2,3,4-tetrahydronaphthalen-2-yl)-7- ethyl-7H-pyrrolo[2,3-c]pyridazine-3- carboxamide  11-25¹¹

437 (CD₃OD, 300 MHz) δ(ppm): 8.57 (s, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.48 (d, J = 8.4 Hz, 1H), 6.34 (s, 1H), 4.26-4.21 (m, 1H), 3.56-3.41 (m, 3H), 3.13-3.08 (m, 2H), 3.08-2.68 (m, 4H), 2.69 (s, 3H), 2.53 (s, 3H), 2.36-2.30 (m, 1H), 2.18-1.48 (m, 3H). 7-amino-3-methyl-N-((S)-6-((S)-3- (methylamino)pyrrolidin-1-yl)- 1,2,3,4-tetrahydronaphthalen-2- yl)thieno[2,3-b]pyrazine-6- carboxamide  11-26¹¹

437 (CD₃OD, 300 MHz) δ(ppm): 8.57 (s, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.48 (d, J = 8.4 Hz, 1H), 6.41 (s, 1H), 4.26-4.21 (m, 1H), 3.76-3.74 (m, 1H), 3.54-3.41 (m, 2H), 3.37-3.34 (m, 1H), 3.29-3.27 (m, 1H), 3.03-2.90 (m, 3H), 2.81-2.67 (m, 7H), 2.44-2.41 (m, 1H), 2.15-2.11 (m, 2H), 1.87-1.83 (m, 1H). 7-amino-3-methyl-N-((R)-6-((S)-3- (methylamino)pyrrolidin-1-yl)- 1,2,3,4-tetrahydronaphthalen-2- yl)thieno[2,3-b]pyrazine-6- carboxamide  11-27¹²

437 (CD₃OD, 400 MHz) δ(ppm): 8.58 (s, 1H), 6.92 (d, J = 8.0 Hz, 1H), 6.42 (d, J = 8.0 Hz, 1H), 6.34 (s, 1H), 4.28-4.23 (m, 1H), 3.51-3.43 (m, 1H), 3.41-3.33 (m, 2H), 3.28-3.24 (m, 1H), 3.15-3.08 (m, 1H), 3.01-2.86 (m, 3H), 2.79-2.70 (m, 1H), 2.69 (s, 3H), 2.44 (s, 3H), 2.31-2.25 (m, 1H), 2.17-2.11 (m, 1H), 7-amino-3-methyl-N-((S)-6-((R)-3- 1.95-1.81 (m, 2H). (methylamino)pyrrolidin-1-yl)- 1,2,3,4-tetrahydronaphthalen-2- yl)thieno[2,3-b]pyrazine-6- carboxamide  11-28¹²

437 (CD₃OD, 400 MHz) δ(ppm): 8.58 (s, 1H), 6.92 (d, J = 8.0 Hz, 1H), 6.42 (d, J = 8.0 Hz, 1H), 6.34 (s, 1H), 4.32-4.26 (m, 1H), 3.51-3.45 (m, 1H), 3.41-3.33 (m, 2H), 3.28-3.24 (m, 1H), 3.11-3.08 (m, 1H), 3.01-2.86 (m, 3H), 2.79-2.73 (m, 1H), 2.69 (s, 3H), 2.45 (s, 3H), 2.29-2.25 (m, 1H), 2.14-2.11 (m, 1H), 7-amino-3-methyl-N-((R)-6-((R)-3- 1.95-1.81 (m, 2H). (methylamino)pyrrolidin-1-yl)- 1,2,3,4-tetrahydronaphthalen-2- yl)thieno[2,3-b]pyrazine-6- carboxamide  11-29¹³

435 (DMSO-d₆, 400 MHz) δ(ppm): 8.65 (s, 1H), 7.80 (d, J = 8.0 Hz, 1H), 6.92 (br s, 2H), 6.85 (d, J = 8.40 Hz, 1H), 6.37-6.34 (br s, 1H), 6.26 (s, 1H), 4.25-4.23 (m, 1H), 4.19-4.06 (m, 1H), 3.56-3.54 (m, 1H), 3.46-3.44 (m, 1H), 2.97-2.71 (m, 7H), 2.68 (s, 3H), 2.20 (br s, 1H), 2.02-1.92 (m, 1H), 1.82- N-((S)-6-((1S,4S)-2,5-diaza- 1.71 (m, 2H), 1.65-1.52 (m, 1H). bicyclo[2.2.1]heptan-2-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-7-amino- 3-methylthieno[3,2-b]pyrazine-6- carboxamide  11-30¹³

435 (DMSO-d₆, 400 MHz) δ(ppm): 8.65 (s, 1H), 7.80 (d, J = 8.0 Hz, 1H), 6.92 (br s, 2H), 6.85 (d, J = 8.4 Hz, 1H), 6.37-6.34 (br s, 1H), 6.26 (s, 1H), 4.25-4.23 (m, 1H), 4.19-4.05 (m, 1H), 3.56-3.54 (m, 1H), 3.49-3.42 (m, 1H), 2.99-2.71 (m, 7H), 2.65 (s, 3H), 2.20 (br s, 1H), 2.01-1.92 (m, 1H), 1.81- N-((R)-6-((1S,4S)-2,5- 1.69 (m, 2H), 1.64-1.57 (m, 1H). diazabicyclo[2.2.1]heptan-2-yl)- 1,2,3,4-tetrahydronaphthalen-2-yl)-7- amino-3-methylthieno[2,3- b]pyrazine-6-carboxamide  11-31¹⁴

435 (DMSO-d₆, 400 MHz) δ(ppm): 8.65 (s, 1H). 7.81 (d, J = 7.6 Hz, 1H), 6.93 (s, 2H) 6.85 (d, J = 8.40 Hz, 1H), 6.37-6.34 (m, 1H), 6.26 (d, J = 2.0 Hz, 1H), 4.24 (s, 1H), 4.13-4.10 (m, 1H), 3.56 (s, 1H), 3.47-3.45 (m, 1H), 2.86-2.71 (m, 7H), 2.68-2.65 (m, 4H), 1.98-1.95 (m, 1H), 1.75-1.73 (m, 2H), N-((S)-6-((1R,4R)-2,5-diaza- 1.62-1.58 (m, 1H). bicyclo[2.2.1]heptan-2-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-7-amino- 3-methylthieno[3,2-b]pyrazine-6- carboxamide  11-32¹⁴

435 (DMSO-d₆, 400 MHz) δ(ppm): 8.65 (s, 1H). 7.81 (d, J = 7.6 Hz, 1H), 6.93 (s, 2H) 6.85 (d, J = 8.40 Hz, 1H), 6.37-6.35 (m, 1H), 6.26 (d, J = 1.6 Hz, 1H), 4.24 (s, 1H), 4.13-4.10 (m, 1H), 3.57 (s, 1H), 3.47-3.45 (m, 1H), 2.86-2.71 (m, 7H), 2.68-2.65 (m, 4H), 1.98-1.95 (m, 1H), 1.76-1.72 (m, 2H), N-((R)-6-((1R,4R)-2,5- 1.62-1.60 (m, 1H). diazabicyclo[2.2.1]heptan-2-yl)- 1,2,3,4-tetrahydronaphthalen-2-yl)-7- amino-3-methylthieno[2,3- b]pyrazine-6-carboxamide  11-33¹⁵

428 (DMSO-d₆, 300 MHz) δ(ppm): 7.45 (d, J = 7.8 Hz, 1H), 7.06 (s, 2H), 6.88 (d, J = 8.7 Hz, 1H), 6.68 (d, J = 8.1 Hz, 1H), 6.60 (s, 1H), 4.10-4.00 (m, 1H), 2.95-2.93 (m, 4H), 2.80-2.63 (m, 12H), 1.94-1.91 (m, 1H), 1.74-1.69 (m, 1H). (S)-6-amino-2-methyl-N-(6- (piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)thieno[2,3- d]thiazole-5-carboxamide  11-34¹⁵

428 (DMSO-d₆, 300 MHz) δ(ppm): 7.45 (d, J = 7.8 Hz, 1H), 7.06 (s, 2H), 6.88 (d, J = 8.7 Hz, 1H), 6.68 (d, J = 8.7 Hz, 1H), 6.60 (s, 1H), 4.10-4.00 (m, 1H), 2.95-2.94 (m, 4H), 2.85-2.63 (m, 12H), 1.95-1.91 (m, 1H), 1.76-1.67 (m, 1H). (R)-6-amino-2-methyl-N-(6- (piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)thieno[2,3- d]thiazole-5-carboxamide  11-35¹⁶

434 (CD₃OD, 300 MHz) δ(ppm): 8.65- 8.43 (m, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.04 (d, J = 8.1 Hz, 1H), 6.42-6.40 (m, 2H), 4.34 (d, J = 6.3 Hz, 1H), 4.35-4.15 (m, 1H), 3.75 (d, J = 13.2 Hz, 2H), 3.19 (d, J = 12.9 Hz, 2H), 3.10-2.86 (m, 4H), 2.85- 2.68 (m, 1H), 2.64 (s, 3H), 2.19-2.05 N-((2S)-6-(3,6- (m, 1H), 1.94-1.75 (m, 2H). diazabicyclo[3.1.1]heptan-6-yl)- 1,2,3,4-tetrahydronaphthalen-2-yl)-3- amino-6-methylthieno[2,3- b]pyridine-2-carboxamide  11-36¹⁶

434 (CD₃OD, 300 MHz) δ(ppm): 8.51(s, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 8.1 Hz, 1H), 6.48-6.40 (m, 2H), 4.34 (d, J = 6.0 Hz, 2H), 4.28-4.22 (m, 1H), 3.75 (d, J = 13.2 Hz, 2H), 3.19 (d, J = 12.9 Hz, 2H), 3.17-2.76 (m, 5H), 2.64 (s, 3H), 2.19-2.08 (m, 1H), 1.94- N-((2R)-6-(3,6- 1.79 (m, 2H). diazabicyclo[3.1.1]heptan-6-yl)- 1,2,3,4-tetrahydronaphthalen-2-yl)-3- amino-6-methylthieno[2,3- b]pyridine-2-carboxamide  11-37¹⁷

441 (DMSO-d₆, 300 MHz) δ(ppm): 8.65 (s, 1H), 7.86 (d, J = 7.5 Hz, 1H), 6.93 (s, 2H), 6.58-6.50 (m, 2H), 4.19-4.03 (m, 1H), 3.03-2.73 (m, 11H), 2.65 (s, 3H), 2.61-2.55 (m, 1H), 2.04-1.96 (m, 1H), 1.81-1.69 (m, 1H). (R)-7-amino-N-(8-fluoro-6- (piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-3- methylthieno[2,3-b]pyrazine-6-carboxamide  11-38¹⁷

441 (DMSO-d₆, 300 MHz) δ(ppm): 8.95 (s, 1H), 7.86 (d, J = 7.5 Hz, 1H), 6.93 (s, 2H), 6.58-6.50 (m, 2H), 4.12-4.11 (m, 1H) 3.02-2.72 (m, 11H), 2.65 (s, 3H), 2.57-2.56 (m, 1H), 2.00-1.96 (m, 1H), 1.81-1.69 (m, 1H). (S)-7-amino-N-(8-fluoro-6- (piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-3- methylthieno[2,3-b]pyrazine-6-carboxamide  11-39¹⁸

482 (CD₃OD, 300 MHz) δ(ppm): 8.23 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 6.70-6.64 (m, 2H), 4.30-4.28 (m, 1H), 3.91 (s, 2H), 3.75 (d, J = 11.7 Hz, 2H), 3.21-2.97 (m, 9H), 2.67-2.56 (m, 4H), 2.15-2.06 (m, 1H), 1.93-1.83 (m, 1H). N-((2S)-6-(9-oxa-3,7- diazabicyclo[3.3.1]nonan-3-yl)-8- fluoro-1,2,3,4-tetrahydronaphthalen- 2-yl)-3-amino-6-methylthieno[2,3- b]pyridine-2-carboxamide  11-40¹⁸

482 (CD₃OD, 300 MHz) δ(ppm): 8.20 (d, J = 8.1 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 6.66-6.62 (m, 2H), 4.30-4.28 (m, 1H), 3.88 (s, 2H), 3.72 (d, J = 12.3 Hz, 2H), 3.30-2.95 (m, 9H), 2.64-2.56 (m, 4H), 2.15-2.06 (m, 1H), 1.93-1.83 (m, 1H). N-((2R)-6-(9-oxa-3,7- diazabicyclo[3.3.1]nonan-3-yl)-8- fluoro-1,2,3,4-tetrahydronaphthalen- 2-yl)-3-amino-6-methylthieno[2,3- b]pyridine-2-carboxamide ¹Notes on procedures: In Step 3, the carboxylic acid Intermediate 16 was used. In Step 4, chiral separation was achieved by SFC (Column: Chiralpak IA-SFC-02, 5 × 25 mm, 5 μm; Mobile phase: CO₂ (60%)/IPA(40%); Flow rate: 40 mL/min; Detector: UV 190-500 nm) to provide the precursor to Example 11-3 (RT = 9.8 min, stereochemistry assumed) and the precursor to Example 11-4 (RT = 12.0 min, stereochemistry assumed). ²Notes on procedures: In Step 3, the carboxylic acid Intermediate 19 was used; purification was by prep-HPLC (Column: XBridge Prep C18 OBD, 19 × 150 mm, 5 μm; Mobile phase A: water (10 mM NH₄HCO₃), B: ACN; Gradient: 25% B to 55% B in 7 min). In Step 4, chiral HPLC (Column: Chiralpak IC, 2 × 25 cm, 5 μm; Mobile phase: 50% EtOH/hexanes for 20 min; Flow rate: 16 mL/min) provided the precursor to Example 11-5 (RT = 11.4 min, stereochemistry assumed) and the precursor to Example 11-6 (RT = 17.5 min, stereochemistry assumed). ³Notes on procedures: In Step 4, chiral HPLC (Column: Chiralpak ID, 5 × 25 mm, 5 μm; Mobile phase: 50% EtOH/hexanes; Detector: UV 190-500 nm) provided the precursor to Example 11-7 (RT = 11.6 min, stereochemistry assumed) and the precursor to Example 11-8 (RT = 13.6 min, stereochemistry assumed). ⁴Notes on procedures: Following the amidation, chiral HPLC conditions: Column: Chiralpak AD-H-SL002, 20 × 250 mm, 5 μm; 30% IPA/hexanes; Detector: 190 nm to 500 nm. The stereochemistry of the separated enantiomers were arbitrarily assigned. Following the boc-deprotection step, prep-HPLC conditions: Column: XBridge Shield RP18 OBD, 130 Å, 5 μm, 19 × 150 mm; Mobile phase: water (10 mM NH₄HCO₃), ACN (25% ACN to 55% over 7 min). ⁵Notes on procedures: In Step 1, the bromide Intermediate 11-1 was used. In Step 3, the crude racemate was purified by reverse-phase chromatography: Column: C18 silica gel; Mobile Phase, A: 10 mM NH₄HCO₃ in H₂O, B: ACN with 0% to 90% B in 30 min. The enantiomers were separated by chiral HPLC: Column: Phenomenex Lux 5 μm Cellulose-4 AXIA Packed, 2.12 × 25 cm, 5 μm; 50% EtOH/hexanes for 24 min. The stereochemistry of the separated enantiomers were arbitrarily assigned. Following the boc-deprotection each enantiomer was purified by prep-HPLC (Column: XBridge Prep OBD C18, 30 × 150 mm 5 μm; Mobile phase: Water (10 mM NH₄HCO₃ + 0.1% NH₃—H₂O) and ACN (18% ACN to 52% in 7 min)). ⁶Notes on procedures: In Step 1, the bromide Intermediate 11-1 was used. In Step 3, the amidation utilized HOBt, EDCI as the coupling agents with Et₃N as the base and DMF solvent. The crude racemate was purified by prep-HPLC: Column: SunFire Prep C18, 19 × 150 mm; Mobile phase A: water (0.05% NH₄HCO₃), B: ACN (55% ACN to 90% in 7 min). The enantiomers were separated by chiral HPLC using: Column: Phenomenex Lux 5u Cellulose-4, AXIA Packed, 250 × 21.2 mm, 5 μm; Mobile Phase: 50% EtOH/hexanes for 19 min. The stereochemistry of the separated enantiomers were arbitrarily assigned. After the boc-deprotection step, each enantiomer was purified by prep-HPLC: Column: XBridge Prep C18 OBD, 5 μm, 19 × 150 mm; Mobile phase: Water (10 mM NH₄HCO₃) and ACN (35% ACN up to 60% in 5 min). ⁷Notes on procedures: In Step 1, the bromide Intermediate 44 and Ruphos Pd G3 as the catalyst were used. In Step 4, the 4 enantiomers were separated by chiral HPLC using the chiral column Cellulose SB and an eluent gradient of 0% to 5% EtOH/MTBE (0.1% Et₂NH). Stereochemistry of the separated enantiomers were arbitrarily assigned. ⁸Notes on procedures: In Step 4, the enantiomers were separated by chiral HPLC using the chiral column Chiralpak ID and mobile phase MeOH. Stereochemistry of the separated enantiomers were arbitrarily assigned. ⁹Notes on procedures: The enantiomers were separated after the Boc deprotection rather than in Step 4, by chiral HPLC using the chiral column Phenomenex Lux 5 μm Cellulose-4 and mobile phase 50% EtOH/hexanes. Stereochemistry of the separated enantiomers were arbitrarily assigned. ¹⁰Notes on procedures: In Step 3, the carboxylic acid Intermediate 26 was used. In Step 4, the enantiomers were separated by chiral HPLC using the chiral column Phenomenex Lux 5 μm Cellulose-4 and mobile phase 50% EtOH/hexanes. Stereochemistry of the separated enantiomers were arbitrarily assigned. ¹¹Notes on procedures: In Step 1, tert-butyl N-methyl-N-[(3S)-pyrrolidin-3-yl]carbamate was used. In Step 4, the enantiomers were separated by chiral HPLC using the chiral column Chiralpak IA and mobile phase 35% EtOH/hexanes. Stereochemistry at the tetrahydronaphthalene amide was arbitrarily assigned. ¹²Notes on procedures: In Step 1, tert-butyl N-methyl-N-[(3R)-pyrrolidin-3-yl]carbamate was used. In Step 4, the enantiomers were separated by chiral HPLC using the chiral column (R,R)-Whelk-O1-Kromasil and mobile phase 30% DCM/EtOH. Stereochemistry at the tetrahydronaphthalene amide was arbitrarily assigned. ¹³Notes on procedures: In Step 1, tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate and Ruphos Pd G3 as the catalyst were used. In Step 4, the enantiomers were separated by chiral HPLC using the chiral column Chiralpak ID and an eluent gradient of 60% to 65% MeOH/DCM. Stereochemistry at the tetrahydronaphthalene amide was arbitrarily assigned. ¹⁴Notes on procedures: In Step 1, tert-butyl (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate and Ruphos Pd G3 as the catalyst were used. In Step 4, the enantiomers were separated by chiral HPLC using the chiral column Chiralpak AD-H-SL001 and mobile phase 40% IPA/hexanes (0.1% Et₂NH). Stereochemistry at the tetrahydronaphthalene amide was arbitrarily assigned. ¹⁵Notes on procedures: In Step 3, the carboxylic acid Intermediate 24 was used. In Step 4, the enantiomers were separated by SFC using the chiral column Phenomenex Lux 5 μm Cellulose-4 and mobile phase 60% EtOH/hexanes. Stereochemistry of the separated enantiomers were arbitrarily assigned. ¹⁶Notes on procedures: Example 11 Method 2 was used. In Step 1, Ruphos Pd G3 was used as the catalyst. ¹⁷Notes on procedures: In Step 1, the bromide Intermediate 11-1 was used. In Step 4, the enantiomers were separated by SFC using the chiral column Phenomenex Lux 5 μm Cellulose-4 and mobile phase 50% CO₂/EtOH:ACN (1:1). Stereochemistry of the separated enantiomers were arbitrarily assigned. ¹⁸Notes on procedures: In Step 1, the bromide Intermediate 11-1 and Ruphos Pd G3 as the catalyst were used. In Step 4, the enantiomers were separated by chiral HPLC using the chiral column Phenomenex Lux 5 μm Cellulose-4 and mobile phase 50% EtOH/hexanes. Stereochemistry of the separated enantiomers were arbitrarily assigned.

Example 12-1. N-((2S)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)-6-amino-2-methylthieno[2,3-d]thiazole-5-carboxamide and Example 12-2. N-((2R)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)-6-amino-2-methylthieno[2,3-d]thiazole-5-carboxamide

Step 1. Tert-Butyl 3-(6-(6-amino-2-methylthieno[2,3-d]thiazole-5-carboxamido)-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

A solution of tert-butyl 3-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 0.42 mmol), Intermediate 23 methyl 6-amino-2-methylthieno[2,3-d]thiazole-5-carboxylate (98 mg, 0.43 mmol), and AlMe₃ (1M in toluene, 1.7 mL, 1.7 mmol) in toluene (6 mL) was stirred overnight at 100° C. After cooling to room temperature, the reaction was quenched by the addition of 10 mL of methanol. The solids were filtered away and the filtrate was concentrated under vacuum. Purification by silica gel chromatography (eluting with gradient 1:3-1:1 EtOAc/pet. ether) afforded tert-butyl 3-(6-(6-amino-2-methylthieno[2,3-d]thiazole-5-carboxamido)-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a white solid. MS: (ESI, m/z): 554 [M+H]⁺.

Step 2. Tert-Butyl 3-((S)-6-(6-amino-2-methylthieno[2,3-d]thiazole-5-carboxamido)-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and tert-Butyl 3-((R)-6-(6-amino-2-methylthieno[2,3-d]thiazole-5-carboxamido)-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

The racemic mixture of tert-butyl 3-(6-(6-amino-2-methylthieno[2,3-d]thiazole-5-carboxamido)-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate was separated by chiral HPLC (Column: Phenomenex Lux cellulose-4, AXIA Packed, 250×21.2 mm, 5 μm; Mobile phase: 50% Hexanes:EtOH for 21 min) to afford the title compounds as follows: tert-butyl 3-((S)-6-(6-amino-2-methylthieno[2,3-d]thiazole-5-carboxamido)-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as white solid (first eluting isomer, RT=12.4 min, stereochemistry assumed) and tert-butyl 3-((R)-6-(6-amino-2-methylthieno[2,3-d]thiazole-5-carboxamido)-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as white solid (second eluting isomer, RT=16.3 min, stereochemistry assumed). MS: (ESI, m/z): 554 [M+H]⁺.

Step 3. N-((2S)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)-6-amino-2-methylthieno[2,3-d]thiazole-5-carboxamide

A solution of tert-butyl 3-((S)-6-(6-amino-2-methylthieno[2,3-d]thiazole-5-carboxamido)-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40 mg, 0.07 mmol) and TFA (1 mL) in DCM (5 mL) was stirred for 30 min at room temperature. The resulting solution was concentrated under vacuum. The residue was diluted with 2 mL of DCM. The pH value of the solution was adjusted to 10 with a solution of ammonia in methanol (7 M). The resulting mixture was concentrated under vacuum. Purification by prep-HPLC (Column:) (Bridge BEH C18 OBD, 130 Å, 19×150 mm, 5 μm; Mobile phase A: water (10 mM NH₄HCO₃), B: ACN; Gradient: 25% B to 45% B over 8 min) afforded N-((2S)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)-6-amino-2-methylthieno[2,3-d]thiazole-5-carboxamide as a white solid. ¹H NMR (CD₃OD, 400 MHz) δ (ppm): 6.96 (d, J=8.5 Hz, 1H), 6.72-6.65 (m, 1H), 6.62 (s, 1H), 4.38-4.19 (m, 1H), 3.72 (s, 2H), 3.50 (s, 2H), 3.04-2.81 (m, 8H), 2.85-2.67 (m, 1H), 2.11 (d, J=12.0 Hz, 1H), 2.03-1.91 (m, 4H), 1.82-1.65 (m, 1H). MS: (ESI, m/z): 454 [M+H]⁺.

Step 4. N-((2R)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)-6-amino-2-methylthieno[2,3-d]thiazole-5-carboxamide

A solution of tert-butyl 3-((R)-6-(6-amino-2-methylthieno[2,3-d]thiazole-5-carboxamido)-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50 mg, 0.09 mmol) and TFA (1 mL) in DCM (5 mL) was stirred for 30 min at room temperature. The resulting solution was concentrated under vacuum. The residue was diluted with 2 mL of DCM. The pH value of the solution was adjusted to 10 with a solution of ammonia in methanol (7 M). The resulting mixture was concentrated under vacuum. Purification by prep-HPLC (Column:) (Bridge BEH C18 OBD, 130 Å, 19×150 mm, 5 μm; Mobile phase A: water (10 mM NH₄HCO₃), B: ACN; Gradient: 30% B to 55% B over 7 min) afforded N-((2R)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)-6-amino-2-methylthieno[2,3-d]thiazole-5-carboxamide as a white solid. ¹H NMR (CD₃OD, 400 MHz) δ (ppm): 6.95 (d, J=8.4 Hz, 1H), 6.72-6.65 (m, 1H), 6.61 (d, J=2.3 Hz, 1H), 4.38-4.21 (m, 1H), 3.70 (s, 2H), 3.53-3.31 (m, 2H), 3.04-2.81 (m, 8H), 2.81-2.71 (m, 1H), 2.15-2.03 (m, 1H), 2.02-1.85 (m, 4H), 1.84-1.67 (m, 1H). MS: (ESI, m/z): 454 [M+H]⁺.

Example 13-1. N-((3R)-7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5,8-difluorochroman-3-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide and Example 13-2. N-((3S)-7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5,8-difluorochroman-3-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide

Step 1. Tert-Butyl 3-(3-(((benzyloxy)carbonyl)amino)-5-fluorochroman-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

A mixture of Intermediate 15-1 tert-butyl 3-(3-amino-5-fluoro-3,4-dihydro-2H-1-benzopyran-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (210 mg, 0.53 mmol), benzyl chloroformate (143 mg, 0.120 mL, 0.80 mmol), potassium carbonate (200 mg, 1.45 mmol), in ethyl acetate (2 mL) and water (2 mL) was stirred for 30 min at 20° C. The mixture was concentrated under vacuum to a crude product that was purified by silica gel chromatography (pet. ether/EtOAc=5:1) to afford tert-butyl 3-(3-[[(benzyloxy) carbonyl]amino]-5-fluoro-3,4-dihydro-2H-1-benzopyran-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a white solid.

MS: (ESI, m/z): 512 [M+H]⁺.

Step 2. Tert-Butyl 3-(3-[[(benzyloxy)carbonyl]amino]-5,8-difluoro-3,4-dihydro-2H-1-benzopyran-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and tert-butyl 3-(3-(((benzyloxy)carbonyl)amino)-5,6-difluorochroman-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl 3-(3-[[(benzyloxy)carbonyl]amino]-5-fluoro-3,4-dihydro-2H-1-benzopyran-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (350 mg, 0.65 mmol), Selectfluor (267 mg, 0.75 mmol), DCM (5 mL) and methanol (5 mL). The resulting solution was stirred for 24 h at 25° C., then the resulting mixture was concentrated under vacuum to afford a crude residue that was purified by column chromatography eluting with ethyl acetate/pet. ether (4:1) to afford tert-butyl 3-(3-[[(benzyloxy)carbonyl]amino]-5,8-difluoro-3,4-dihydro-2H-1-benzopyran-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and tert-butyl 3-(3-(((benzyloxy)carbonyl)amino)-5,6-difluorochroman-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate that were carried on separately to the desired final examples. Both intermediates have MS: (ESI, m/z): 530 [M+H]⁺.

Step 3. Tert-Butyl 3-(3-amino-5,8-difluoro-3,4-dihydro-2H-1-benzopyran-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Into a flask purged and maintained with nitrogen was added tert-butyl 3-(3-[[(benzyloxy)carbonyl]amino]-5,8-difluoro-3,4-dihydro-2H-1-benzopyran-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (80 mg, 0.15 mmol) and methanol (6 mL). Palladium on carbon (80 mg) was added, then the resulting suspension was stirred for 1 h at 18° C. The solids were removed by filtration over Celite, and the resulting filtrate was concentrated under vacuum to afford tert-butyl 3-(3-amino-5,8-difluoro-3,4-dihydro-2H-1-benzopyran-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as yellow oil. MS: (ESI, m/z): 396 [M+H]⁺.

Step 4. 3-(3-[3-Amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,8-difluoro-3,4-dihydro-2H-1-benzopyran-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Into a 50-mL round-bottom flask was added tert-butyl 3-(3-amino-5,8-difluoro-3,4-dihydro-2H-1-benzopyran-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (55 mg, 0.14 mmol), DMA (2 mL), 3-amino-6-methylthieno[2,3-b]pyridine-2-carboxylic acid (29 mg, 0.14 mmol), DIEA (54 mg, 0.074 mL, 0.42 mmol), EDCI (53 mg, 0.28 mmol), and HOBt (38 mg, 0.28 mmol). The resulting solution was stirred for overnight at 18° C. The resulting mixture was purified by reversed chromatograpy (Column: C₁₈ silica gel; Mobile phase: 10 mM NH₄HCO₃ in H₂O/ACN=100/0 increasing to 30/70 within 30 min. The combined fractions were concentrated under vacuum to afford tert-butyl 3-(3-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,8-difluoro-3,4-dihydro-2H-1-benzopyran-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. MS: (ESI, m/z): 586 [M+H]⁺.

Step 5. N-((3R)-7-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-5,8-difluorochroman-3-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide and N-((3S)-7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5,8-difluorochroman-3-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide

Into a 25-mL round-bottom flask was added tert-butyl 3-(3-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,8-difluoro-3,4-dihydro-2H-1-benzopyran-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30 mg, 0.05 mmol), DCM (1.5 mL), and trifluoroacetic acid (0.5 mL). The resulting solution was stirred for 1 h at 18° C. The resulting mixture was concentrated under vacuum to afford racemic 3-amino-N-(7-[3,8-diazabicyclo[3.2.1]octan-3-yl]-5,8-difluoro-3,4-dihydro-2H-1-benzopyran-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide; trifluoroacetic acid salt as a yellow solid. MS: (ESI, m/z): 486 [M+H]⁺.

Chiral Separation:

3-amino-N-(7-[3,8-diazabicyclo[3.2.1]octan-3-yl]-5,8-difluoro-3,4-dihydro-2H-1-benzopyran-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide; trifluoroacetic acid (28 mg, 0.05 mmol) was separated by chiral HPLC (Column: ChiralArt Cellulose-SB, 2×25 cm, 5 μm; Mobile Phase A: hexanes (0.1% Et₂NH), B: EtOH; Gradient: 40% B for 19 min). The first eluting isomer (RT=14.40 min) was concentrated then lyophilized to afford 3-amino-N-[(3R)-7-[3,8-diazabicyclo[3.2.1]octan-3-yl]-5,8-difluoro-3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide (stereochemistry arbitrarily assigned) as a yellow solid. MS: (ESI, m/z): 486 [M+H]⁺. ¹H NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.32 (d, J=8.4 Hz, 1H), 7.65 (d, J=6.8 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.24 (s, 2H), 6.37-6.33 (m, 1H), 4.35-4.24 (m, 2H), 3.96-3.91 (m, 1H), 3.44 (s, 2H), 3.09-2.80 (m, 6H), 2.58 (s, 3H), 1.82-1.66 (m, 4H).

The second eluting isomer (RT=16.71 min) was concentrated then lyophilized to afford 3-amino-N-[(3S)-7-[3,8-diazabicyclo[3.2.1]octan-3-yl]-5,8-difluoro-3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide (stereochemistry arbitrarily assigned) as a yellow solid. MS: (ESI, m/z): 486 [M+H]⁺. ¹H NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.33 (d, J=8.4 Hz, 1H), 7.66 (d, J=7.2 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.24 (s, 2H), 6.39-6.35 (m, 1H), 4.33-4.24 (m, 2H), 3.96-3.92 (m, 1H), 3.58 (s, 2H), 3.11-2.73 (m, 6H), 2.58 (s, 3H), 1.90-1.69 (m, 4H), 1.23 (s, 1H).

The following examples in Table 17 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Examples 13-1 and 13-2.

TABLE 17 LRMS Example m/z Number Structure and Compound Name [M + H]⁺ ¹H NMR 13-3¹

N-((3R)-7-(3,8- diazabicyclo[3.2.1]octan-3-yl)-5,6- difluorochroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2- carboxamide 486 (DMSO-d6, 400 MHz) δ (ppm): 8.32 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 7.2 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.23 (s, 2H), 6.16 (d, J = 7.2 Hz, 1H), 4.30-4.26 (m, 1H), 4.16-4.13 (m, 1H), 3.89-3.84 (m, 1H), 3.45 (s, 2H), 3.10- 2.77 (m, 6H), 2.58 (s, 3H), 1.82- 1.77 (m, 4H), 1.25 (s, 1H). 13-4¹

N-((3S)-7-(3,8- diazabicyclo[3.2.1]octan-3-yl)-5,6- difluorochroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2- carboxamide 486 (DMSO-d6, 400 MHz) δ (ppm): 8.32 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 6.8 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.23 (s, 2H), 6.17 (d, J = 6.4 Hz, 1H), 4.30-4.24 (m, 1H), 4.16-4.13 (m, 1H), 3.89-3.84 (m, 1H), 3.49 (s, 2H), 3.11- 2.77 (m, 6H), 2.58 (s, 3H), 1.84- 1.68 (m, 4H), 1.23 (s, 1H). 13-5²

(R)-3-amino-N-(6-chloro-7- (piperazin-1-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 458, 460 (DMSO-d6, 300 MHz) δ (ppm): 8.36 (s, 1H), 8.31 (d, J = 8.3 Hz, 1H), 7.72 (t, J = 5.6 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 7.17-7.12 (m, 4H), 6.94-6.70 (m, 2H), 5.02 (t, J = 4.5 Hz, 1H), 3.98-4.03 (m, 1H), 3.72-3.91 (m, 5H), 3.42-3.35 (m, 2H), 2.78-2.73 (m, 2H), 2.58 (s, 3H), 2.45-2.27 (m, 2H). 13-6²

(S)-3-amino-N-(6-chloro-7- (piperazin-1-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 458, 460 (DMSO-d6, 300 MHz) δ (ppm): 8.36 (s, 1H), 8.31 (d, J = 8.3 Hz, 1H), 7.72 (t, J = 5.6 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 7.17-7.12 (m, 4H), 6.94-6.70 (m, 2H), 5.02 (t, J = 4.5 Hz, 1H), 3.98-4.03 (m, 1H), 3.72-3.91 (m, 5H), 3.42-3.35 (m, 2H), 2.78-2.73 (m, 2H), 2.58 (s, 3H), 2.45-2.27 (m, 2H). 13-7²

(R)-3-amino-N-(8-chloro-7- (piperazin-1-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 458, 460 (DMSO-d6, 300 MHz) δ (ppm): 8.36 (s, 1H), 8.31 (d, J = 8.3 Hz, 1H), 7.72 (t, J = 5.6 Hz, 1H),7.31 (d, J = 8.3 Hz, 1H), 7.17-7.12 (m, 4H), 6.94-6.70 (m, 2H), 5.02 (t, J = 4.5 Hz, 1H), 3.98-4.03 (m, 1H), 3.72-3.91 (m, 5H), 3.42-3.35 (m, 2H), 2.78-2.73 (m, 2H), 2.58 (s, 3H), 2.45-2.27 (m, 2H). 13-8²

(S)-3-amino-N-(8-chloro-7- (piperazin-1-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 458, 460 (DMSO-d6, 300 MHz) δ (ppm): 8.36 (s, 1H), 8.31 (d, J = 8.3 Hz, 1H), 7.72 (t, J = 5.6 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 7.17-7.12 (m, 4H), 6.94-6.70 (m, 2H), 5.02 (t, J = 4.5 Hz, 1H), 3.98-4.03 (m, 1H), 3.72-3.91 (m, 5H), 3.42-3.35 (m, 2H), 2.78-2.73 (m, 2H), 2.58 (s, 3H), 2.45-2.27 (m, 2H). ¹Notes on procedures: Chiral separation conditions: Column: ChiralArt Cellulose-SB, 2 × 25 cm, 5 μm; mobile phase: 30% EtOH (8 mM NH₃ in MeOH)/MTBE for 15 min. ²Notes on procedures: The halogenation reaction (step 2) was conducted using N-chlorosuccinimide in DCM solvent. The Cbz removal (step 3) was conducted using KOH/MeOH at 80° C. for 3 h. The mixture of chloro regioisomers and enantiomers (4 compounds) was separated after Step 4 using chiral HPLC: Column: XBridge BEH C18 OBD Prep Column, 130 Å, 5 μm, 19 × 150 mm; Mobile phase: water (10 mmol NH₄HCO₃) and ACN (31% ACN up to 53% in 7 min).

Example 14-1. N-((2R)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5-cyano-1,2,3,4-tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide Example 14-2. N-((2S)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5-cyano-1,2,3,4-tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide Example 14-3. N-((2R)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-cyano-1,2,3,4-tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide and Example 14-4. N-((2S)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-cyano-1,2,3,4-tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide

Step 1. Mixture of racemic tert-butyl 3-(6-(((benzyloxy)carbonyl)amino)-1-bromo-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and racemic tert-butyl 3-(6-(((benzyloxy)carbonyl)amino)-3-bromo-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Into a 250-mL round-bottom flask was added tert-butyl 3-(6-[[(benzyloxy)carbonyl]amino]-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.2 g, 2.44 mmol) and DCM (96 mL). This was followed by the addition of a solution of NBS (478 mg, 2.69 mmol) in DCM (24 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at 20° C., then was quenched by the addition of water (20 mL).

The resulting solution was extracted with DCM (3×30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford a residue that was purified by silica gel chromatography eluting with ethyl acetate/pet. ether (PE/EA=100:1 to 5:1) to afford a mixture of tert-butyl 3-(6-[[(benzyloxy)carbonyl]amino]-3-bromo-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and tert-butyl 3-(6-[[(benzyloxy)carbonyl]amino]-1-bromo-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. MS: (ESI, m/z): 572 [M+H]⁺.

Step 2. Mixture of racemic tert-butyl 3-(6-[[(benzyloxy)carbonyl]amino]-3-cyano-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and tert-butyl 3-(6-[[(benzyloxy)carbonyl]amino]-1-cyano-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Into a 20-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was added a mixture of tert-butyl 3-(6-[[(benzyloxy)carbonyl]amino]-3-bromo-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and tert-butyl 3-(6-[[(benzyloxy)carbonyl]amino]-1-bromo-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (460 mg, 0.81 mmol), Zn(CN)₂ (93 mg, 0.80 mmol), Pd(PPh₃)₄ (93 mg, 0.08 mmol), and N,N-dimethylformamide (9 mL). The resulting mixture was irradiated with microwave for 1 h at 120° C. The reaction was cooled to room temperature and quenched by the addition of 20 mL of water. The resulting solution was extracted with ethyl acetate (3×15 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford a residue that was purified by silica gel chromatography and eluted with 100:1 to 2:1 ethyl acetate/pet. ether to afford a mixture of tert-butyl 3-(6-[[(benzyloxy)carbonyl]amino]-3-cyano-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and tert-butyl 3-(6-[[(benzyloxy)carbonyl]amino]-1-cyano-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as yellow oil. MS: (ESI, m/z): 517 [M+H]⁺.

Step 3. Mixture of racemic tert-butyl 3-(6-amino-3-cyano-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and racemic tert-butyl 3-(6-amino-1-cyano-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Into a 50-mL round-bottom flask purged and maintained with nitrogen, was added a mixture of tert-butyl 3-(6-[[(benzyloxy)carbonyl]amino]-3-cyano-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and tert-butyl 3-(6-[[(benzyloxy)carbonyl]amino]-1-cyano-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.58 mmol), ethanol (20 mL), and Palladium carbon (300 mg). The resulting suspension was stirred for 1 h at 20° C. under hydrogen atmosphere. The solids were removed by filtration over celite and the filtrate was concentrated under vacuum to afford a crude residue that was purified by silica gel chromatography and eluted with DCM/methanol (DCM/MeOH=10:1) to afford a mixture of tert-butyl 3-(6-amino-3-cyano-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and tert-butyl 3-(6-amino-1-cyano-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as yellow oil. MS: (ESI, m/z): 383 [M+H]⁺.

Step 4. Tert-Butyl 3-((R)-6-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-1-cyano-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Peak A, Enantiomer 1) Tert-butyl 3-((S)-6-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-1-cyano-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Peak A, Enantiomer 2) Tert-butyl 3-((R)-6-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-3-cyano-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Peak B, Enantiomer 1) Tert-butyl 3-((S)-6-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-3-cyano-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Peak B, Enantiomer 2)

Into a 100-mL round-bottom flask was placed the mixture of tert-butyl 3-(6-amino-1-cyano-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and tert-butyl 3-(6-amino-3-cyano-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diaz abicyclo[3.2.1]octane-8-carboxylate (150 mg, 0.39 mmol), EDCI (90 mg, 0.47 mmol), HOBt (63 mg, 0.47 mmol), DIEA (152 mg, 1.18 mmol), N,N-dimethylformamide (10 mL), and 3-amino-6-methylthieno[2,3-b]pyridine-2-carboxylic acid (98 mg, 0.47 mmol). The resulting solution was stirred for 2 h at 20° C., then was quenched by the addition of 20 mL of water. The solids were collected by filtration, and the solids were purified by prep-HPLC (Column: XBridge BEH C18 OBD, 5 μm, 19×150 mm; Mobile phase: water (10 mM NH₄HCO₃), ACN (55% ACN up to 70% over 7 min)).

This mixture was then further purified by chiral HPLC (Column: Chiralpak OD-H, 5 20×250 mm; Mobile phase A: hexanes, B: EtOH, 50% B). This resulted in a single regioisomer peak A: (RT=8.45 min) and single regioisomer peak B: (RT=12.91 min).

The peak A was further purified by chiral HPLC (Column: Chiralpak IC, 5 μm, 20×250 mm; Mobile phase A: hexanes, B: EtOH, 50% B). This resulted in peak A, enantiomer 1: (RT=15.55 min) as a yellow solid and peak A, enantiomer 2: (RT=21.10 min) as a yellow solid. Stereochemistry of the separated peak A enantiomers were arbitrarily assigned. MS (for both enantiomers): (ESI, m/z): 573 [M+H]⁺.

The peak B was further purified by chiral HPLC (Column: Chiralpak IB, 5 μm 20×250 mm; Mobile phase A: hexanes, B: EtOH, 50% B). This resulted in peak B, enantiomer 1: (RT=7.65 min) as a yellow solid and peak B, enantiomer 2: (RT=9.22 min) as a yellow solid. Stereochemistry of the separated peak B enantiomers were arbitrarily assigned. MS (for both enantiomers): (ESI, m/z): 573 [M+H]⁺.

Step 5. N-((2R)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5-cyano-1,2,3,4-tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide N-((2S)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5-cyano-1,2,3,4-tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide N-((2R)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-cyano-1,2,3,4-tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide N-((2S)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-cyano-1,2,3,4-tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide

Representative Procedure and Spectra for the First Isomer:

Into a 50-mL round-bottom flask, was added tert-butyl 3-[(6R)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-1-cyano-5,6,7,8-tetrahydronaphthalen-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30 mg, 0.05 mmol), DCM (5 mL), and TFA (1 mL). The resulting solution was stirred for 1 h at 20° C., then was concentrated under vacuum to afford a crude residue that was diluted with 5 mL of DCM. The pH of the solution was adjusted to 8 with NH₃ in MeOH (7 M), then the resulting mixture was concentrated under vacuum to a residue that was purified by prep-HPLC (Column: XBridge BEH C18 OBD Prep Column, 130 Å, 5 μm 19×150 mm; Mobile phase: water (10 mmol NH₄HCO₃), ACN (35% ACN up to 56% over 7 min)) to afford N-((2R)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5-cyano-1,2,3,4-tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide as a light yellow solid. ¹H NMR (400 MHz, MeOH-d₄) δ (ppm): 8.20 (d, J=8.3 Hz, 1H), 7.29-7.30 (m, 2H), 6.94 (d, J=8.5 Hz, 1H), 4.21-4.24 (m, 1H), 3.55 (s, 2H), 3.20-3.27 (m, 2H), 2.91-3.19 (m, 5H), 2.79-2.80 (m, 1H), 2.64 (s, 3H), 2.18-2.20 (m, 3H), 1.79-1.94 (m, 3H). MS: (ESI, m/z): 473 [M+H]⁺.

The following examples in Table 18 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Example 14-1.

TABLE 18 LRMS Example m/z Number Structure and Compound Name [M + H]⁺ ¹H NMR 14-2

N-((2S)-6-(3,8- diazabicyclo[3.2.1]octan-3-yl)-5- cyano-1,2,3,4-tetrahydronaphthalen- 2-yl)-3-amino-6-methylthieno[2,3- b]pyridine-2-carboxamide 473 (CD₃OD, 400 MHz) δ (ppm): 8.20 (d, J = 8.4 Hz, 1H), 7.31-7.28 (m, 2H), 6.94 (d, J = 8.8 Hz, 1H), 4.27-4.20 (m, 1H), 3.56 (s, 2H), 3.31-3.27 (m, 2H), 3.16-2.94 (m, 5H), 2.84-2.77 (m, 1H), 2.64 (s, 3H), 2.21-2.19 (m, 3H), 1.92-1.82 (m, 3H). 14-3

N-((2R)-6-(3,8- diazabicyclo[3.2.1]octan-3-yl)-7- cyano-1,2,3,4-tetrahydronaphthalen- 2-yl)-3-amino-6-methylthieno[2,3- b]pyridine-2-carboxamide 473 (CD₃OD, 400 MHz) δ (ppm): 8.20 (d, J = 8.4 Hz, 1H), 7.36-7.29 (m, 2H), 6.88 (s, 1H), 4.27-4.21 (m, 1H), 3.57 (s, 2H), 3.33-3.30 (m, 2H), 3.02-2.95 (m, 5H), 2.81-2.75 (m, 1H), 2.64 (s, 3H), 2.18-2.10 (m, 3H), 1.86-1.79 (m, 3H). 14-4

N-((2S)-6-(3,8- diazabicyclo[3.2.1]octan-3-yl)-7- cyano-1,2,3,4-tetrahydronaphthalen- 2-yl)-3-amino-6-methylthieno[2,3- b]pyridine-2-carboxamide 473 (CD₃OD, 400 MHz) δ (ppm): 8.20 (d, J = 8.4 Hz, 1H), 7.37-7.30 (m, 2H), 6.88 (s, 1H), 4.27-4.21 (m, 1H), 3.60 (s, 2H), 3.34-3.30 (m, 2H), 3.03-2.97 (m, 5H), 2.81-2.75 (m, 1H), 2.64 (s, 3H), 2.20-2.10 (m, 3H), 1.87-1.80 (m, 3H). 14-5

N-((2R)-6-(3,8- diazabicyclo[3.2.1]octan-3-yl)-5- cyano-1,2,3,4-tetrahydronaphthalen- 2-yl)-7-amino-3-methylthieno[2,3- b]pyrazine-6-carboxamide 474 (CD₃OD, 300 MHz) δ (ppm): 8.54 (s, 1H), 7.33 (s, 1H), 6.85 (s, 1H), 4.28- 4.18 (m, 1H), 3.61-3.51 (m, 2H), 3.35- 3.31 (m, 2H), 3.05-2.92 (m, 5H), 2.83- 2.69 (m, 1H), 2.65 (s, 3H), 2.17-2.09 (m, 3H), 1.98-1.70 (m, 3H). 14-6

N-((2S)-6-(3,8- diazabicyclo[3.2.1]octan-3-yl)-5- cyano-1,2,3,4-tetrahydronaphthalen- 2-yl)-7-amino-3-methylthieno[2,3- b]pyrazine-6-carboxamide 474 (CD₃OD, 300 MHz) δ (ppm): 8.55 (s, 1H), 7.28 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 4.27-4.19 (m, 1H), 3.61-3.59 (m, 2H), 3.33-3.31 (m, 2H), 3.18-2.88 (m, 5H), 2.83-2.74 (m, 1H), 2.65 (s, 3H), 2.25-2.12 (m, 3H), 1.92- 1.75 (m, 3H). 14-7

N-((2R)-6-(3,8- diazabicyclo[3.2.1]octan-3-yl)-7- cyano-1,2,3,4-tetrahydronaphthalen- 2-yl)-7-amino-3-methylthieno[2,3- b]pyrazine-6-carboxamide 474 (CD₃OD, 400 MHz) δ (ppm): 8.58 (s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 4.35-4.18 (m, 1H), 3.62-3.59 (m, 2H), 3.35-3.32 (m, 2H), 3.15-2.96 (m, 5H), 2.86-2.77 (m, 1H), 2.68 (s, 3H), 2.28-2.18 (m, 3H), 1.96- 1.82 (m, 3H). 14-8

N-((2S)-6-(3,8- diazabicyclo[3.2.1]octan-3-yl)-7- cyano-1,2,3,4-tetrahydronaphthalen- 2-yl)-7-amino-3-methylthieno[2,3- b]pyrazine-6-carboxamide 474 (CD₃OD, 400 MHz) δ (ppm): 8.54 (s, 1H), 7.32 (s, 1H), 6.84 (s, 1H), 4.28- 4.17 (m, 1H), 3.53-3.49 (m, 2H), 3.28-3.23 (m, 2H), 3.06-2.92 (m, 5H), 2.81-2.70 (m, 1H), 2.64 (s, 3H), 2.18- 2.08 (m, 3H), 1.89-1.75 (m, 3H). 14-9^(1,2)

(R)-3-amino-N-(5-cyano-8-fluoro-6- (piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 465 (DMSO-d₆, 400 MHz) δ (ppm): 8.31 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.18 (s, 2H), 6.86 (d, J = 11.6 Hz, 1H), 4.15 (s, 1H), 3.06-2.87 (m, 11H), 2.67-2.58 (m, 4H), 2.08-1.81 (m, 2H), 1.23 (s, 1H), 1.16-1.12 (m, 1H), 0.86 (s, 1H). 14-10^(1,2)

(S)-3-amino-N-(5-cyano-8-fluoro-6- (piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 465 (DMSO-d₆, 400 MHz) δ (ppm): 8.31 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.23 (s, 2H), 6.87 (d, J = 11.2 Hz, 1H), 4.15 (s, 1H), 3.07-2.82 (m, 11H), 2.78-2.58 (m, 4H), 2.11-1.80 (m, 2H), 1.23 (s, 1H), 1.17-1.13 (m, 1H), 0.86 (s, 1H). 14-11^(1,3)

(R)-7-amino-N-(5-cyano-8-fluoro-6- (piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-3- methylthieno[2,3-b]pyrazine-6- carboxamide 466 (DMSO-d₆, 400 MHz) δ (ppm): 8.65 (s, 1H), 7.92 (br s, 1H), 6.95 (br s, 2H), 6.88 (d, J = 11.6 Hz, 1H), 4.30- 4.10 (m, 1H), 3.10-2.80 (m, 11H), 2.62-2.55 (m, 4H), 2.15-2.00 (m, 1H), 1.90-1.75 (m, 1H). 14-12^(1,3)

(S)-7-amino-N-(5-cyano-8-fluoro-6- (piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-3- methylthieno[2,3-b]pyrazine-6- carboxamide 466 (DMSO-d₆, 400 MHz) δ (ppm): 8.65 (s, 1H), 7.91 (br s, 1H), 6.94 (br s, 2H), 6.88 (d, J = 11.6 Hz, 1H), 4.30- 4.10 (m, 1H), 3.10-2.80 (m, 11H), 2.62-2.55 (m, 4H), 2.15-2.00 (m, 1H), 1.90-1.75 (m, 1H). 14-13^(1,4)

(R)-6-amino-N-(5-cyano-8-fluoro-6- (piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-2- methylthieno[2,3-dlthiazole-5- carboxamide 471 (DMSO-d₆, 400 MHz) δ (ppm): 7.58 (br s, 1H), 7.10 (br s, 2H), 6.85 (d, J = 11.6 Hz, 1H), 4.20-4.05 (m, 1H), 3.04-3.01 (m, 11H), 2.84 (s, 3H), 2.67-2.55 (m, 1H), 2.04-2.03 (m, 1H), 1.81-1.77 (m, 1H). 14-14^(1,4)

(S)-6-amino-N-(5-cyano-8-fluoro-6- (piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-2- methylthieno[2,3-d]thiazole-5- carboxamide 471 (DMSO-d₆, 400 MHz) δ (ppm): 7.58 (br s, 1H), 7.10 (br s, 2H), 6.84 (d, J = 11.6 Hz, 1H), 4.20-4.05 (m, 1H), 3.04-3.01 (m, 11H), 2.84 (s, 3H), 2.67-2.55 (m, 1H), 2.04-2.03 (m, 1H), 1.81-1.77 (m, 1H). 14-15^(1,5)

3-amino-N-[(2S)-5-cyano-8-fluoro-6- {9-oxa-3,7-diazabicyclo[3.3.1]nonan- 3-yl}-1,2,3,4-tetrahydronaphthalen-2- yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide 507 (DMSO-d₆, 400 MHz) δ (ppm): 8.31 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 7.2 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.19 (br s, 2H), 6.95 (d, J = 11.6 Hz, 1H), 4.16-4.14 (m, 1H), 3.71-3.69 (m, 2H), 3.56-3.53 (m, 2H), 3.33-3.30 (m, 2H), 3.15-2.95 (m, 7H), 2.67-2.60 (m, 1H), 2.58 (s, 3H), 2.09-2.05 (m, 1H), 1.88-1.82 (m, 1H). 14-16^(1,5)

3-amino-N-[(2R)-5-cyano-8-fluoro-6- {9-oxa-3,7-diazabicyclo[3.3.1]nonan- 3-yl}-1,2,3,4-tetrahydronaphthalen-2- yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide 507 (DMSO-d₆, 400 MHz) δ (ppm): 8.31 (d, J = 8.0 Hz, 7.69 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.19 (br s, 2H), 6.95 (d, J = 11.6 Hz, 1H), 4.16-4.14 (m, 1H), 3.71-3.69 (m, 2H), 3.53-3.50 (m, 2H), 3.31-3.27 (m, 2H), 3.16-2.95 (m, 7H), 2.67-2.60 (m, 1H), 2.58 (s, 3H), 2.08-2.05 (m, 1H), 1.88-1.82 (m, 1H). 14-17^(1,6)

3-amino-N-[(2S)-5-cyano-6-{3,8- diazabicyclo[3.2.1]octan-3-yl}-8- fluoro-1,2,3,4-tetrahydronaphthalen- 2-yl]-6-methylthieno[2,3-b]pyridine- 2-carboxamide 491 (DMSO-d₆, 300 MHz) δ (ppm): 8.30 (d, J = 8.1 Hz, 1H), 7.66 (d, J = 7.5 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.18 (br s, 2H), 6.78 (d, J = 12.0 Hz, 1H), 4.15-4.14 (m, 1H), 3.44-3.42 (m, 2H), 3.33-3.25 (m, 2H), 3.05-2.82 (m, 5H), 2.61-2.55 (m, 4H), 2.07-2.03 (m, 1H), 1.94-1.75 (m, 3H), 1.66-1.63 (m, 2H). 14-18^(1,6)

3-amino-N-[(2R)-5-cyano-6-{3,8- diazabicyclo[3.2.1]octan-3-yl}-8- fluoro-1,2,3,4-tetrahydronaphthalen- 2-yl]-6-methylthieno[2,3-b]pyridine- 2-carboxamide 491 (DMSO-d₆, 300 MHz) δ (ppm): 8.30 (d, J = 8.1 Hz, 1H), 7.66 (d, J = 7.5 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.18 (br s, 2H), 6.78 (d, J = 11.7 Hz, 1H), 4.15-4.14 (m, 1H), 3.45-3.43 (m, 2H), 3.33-3.25 (m, 2H), 3.05-2.82 (m, 5H), 2.61-2.55 (m, 4H), 2.37 (br s, 1H), 2.07-2.03 (m, 1H), 1.94-1.75 (m, 3H), 1.66-1.63 (m, 2H). 14-19^(1,7)

7-amino-N-[(2S)-5-cyano-6-{3,8- diazabicyclo[3.2.1]octan-3-yl}-8- fluoro-1,2,3,4-tetrahydronaphthalen- 2-yl]-3-methylthieno[2,3-b]pyrazine- 6-carboxamide 492 (DMSO-d₆, 300 MHz) δ (ppm): 8.65 (s, 1H), 7.90 (br s, 1H), 6.94 (br s, 2H), 6.79 (d, J = 11.7 Hz, 1H), 4.18- 4.14 (m, 1H), 3.46-3.44 (m, 2H), 3.32-3.23 (m, 2H), 3.05-2.82 (m, 6H), 2.65 (s, 3H), 2.64-2.56 (m, 1H), 2.08- 1.82 (m, 4H), 1.66-1.64 (m, 2H). 14-20^(1,7)

7-amino-N-[(2R)-5-cyano-6-{3,8- diazabicyclo[3.2.1]octan-3-yl}-8- fluoro-1,2,3,4-tetrahydronaphthalen- 2-yl]-3-methylthieno[2,3-b]pyrazine- 6-carboxamide 492 (DMSO-d₆, 300 MHz) δ (ppm): 8.65 (s, 1H), 7.90 (br s, 1H), 6.94 (br s, 2H), 6.79 (d, J = 12.0 Hz, 1H), 4.18- 4.15 (m, 1H), 3.44-3.42 (m, 2H), 3.32-3.22 (m, 2H), 3.05-2.82 (m, 6H), 2.65 (s, 3H), 2.64-2.56 (m, 1H), 2.08- 1.82 (m, 4H), 1.68-1.64 (m, 2H). 14-21^(1,8)

6-amino-N-[(2S)-5-cyano-6-{3,8- diazabicyclo[3.2.1]octan-3-yl}-8- fluoro-1,2,3,4-tetrahydronaphthalen- 2-yl]-2-methylthieno[2,3- d][1,3]thiazole-5-carboxamide 497 (DMSO-d₆, 400 MHz) (ppm): 7.57 (br s, 1H), 7.11 (br s, 2H), 6.79 (d, J = 12.0 Hz, 1H),4.11 (br s, 1H), 3.45- 3.43 (m, 2H), 3.27-3.22 (m, 2H), 3.04-2.82 (m, 5H), 2.79 (s, 3H), 2.61- 2.52 (m, 1H), 2.05-1.96 (m, 1H), 1.94-1.86 (m, 2H), 1.84-1.76 (m, 1H), 1.66-1.63 (m, 2H). 14-22^(1,8)

6-amino-N-[(2R)-5-cyano-6-{3,8- diazabicyclo[3.2.1]octan-3-yl}-8- fluoro-1,2,3,4-tetrahydronaphthalen- 2-yl]-2-methylthieno[2,3- d][1,3]thiazole-5-carboxamide 497 (DMSO-d₆, 400 MHz) (ppm): 7.59 (br s, 1H), 7.11 (br s, 2H), 6.79 (d, J = 12.0 Hz, 1H), 4.13-4.09 (m, 1H), 3.45-3.44 (m, 2H), 3.27-3.22 (m, 2H), 3.03-2.84 (m, 5H), 2.79 (s, 3H), 2.60- 2.51 (m, 1H), 2.04-1.95 (m, 1H), 1.93-1.90 (m, 2H), 1.81-1.70 (m, 1H), 1.65-1.60 (m, 2H). 12-23^(1,9,10)

3-amino-N-[(2S)-6-[(3S,4S)-3-amino- 4-methoxypyrrolidin-1-yl]-5-cyano- 8-fluoro-1,2,3,4- tetrahydronaphthalen-2-yl]-6- methylthieno[2,3-b]pyridine-2- carboxamide 495 (DMSO-d₆, 400 MHz) δ (ppm): 8.31 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.17 (br s, 2H), 6.48 (d, J = 12.4 Hz, 1H), 4.14-4.08 (m, 1H), 3.84-3.81 (m, 1H), 3.73-3.65 (m, 2H), 3.47-3.41 (m, 1H), 3.38-3.32 (m, 1H), 3.30 (s, 3H), 3.27-3.23 (m, 1H), 3.05-3.00 (m, 1H), 2.92-2.82 (m, 2H), 2.58 (s, 3H), 2.55- 2.51 (m, 1H), 2.07-2.02 (m, 1H), 1.85-1.73 (m, 2H). 12-24^(1,9,10)

3-amino-N-[(2R)-6-[(3S,4S)-3- amino-4-methoxypyrrolidin-1-yl]-5- cyano-8-fluoro-1,2,3,4- tetrahydronaphthalen-2-yl]-6- methylthieno[2,3-b]pyridine-2- carboxamide 495 (DMSO-d₆, 400 MHz) δ (ppm): 8.31 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.17 (br s, 2H), 6.48 (d, J = 12.8 Hz, 1H), 4.14-4.08 (m, 1H), 3.86-3.83 (m, 1H), 3.73-3.66 (m, 2H), 3.45-3.42 (m, 1H), 3.38-3.35 (m, 1H), 3.30 (s, 3H), 3.27-3.23 (m, 1H), 3.05-2.75 (m, 3H), 2.58 (s, 3H), 2.07-2.01 (m, 1H), 1.85- 1.73 (m, 2H). ¹Notes on procedures: In Step 1, only one bromination regioisomer was observed, tert-butyl 4-(6-(((benzyloxy)carbonyl)amino)-1-bromo-4-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl)piperazine-1-carboxylate. ²Notes on procedures: Chiral separation of the enantiomers was performed after Step 5 rather than in Step 4, using the chiral column Chiralpak IA and Mobile Phase 50% EtOH/hexanes (0.1% Et₂NH). Stereochemistry of the separated enantiomers were arbitrarily assigned. ³Notes on procedures: In Step 4, the amide coupling reaction was performed with HBTU and Et₃N in DMA. Chiral separation of the enantiomers was performed after Step 5 rather than in Step 4, using the chiral column Chiralpak IE and Mobile Phase 20% IPA/MTBE (0.1% Et₂NH). Stereochemistry of the separated enantiomers were arbitrarily assigned. ⁴Notes on procedures: In Step 4, the carboxylic acid Intermediate 24 was used. The amide coupling reaction was performed with HBTU and Et₃N in DMA. Chiral separation of the enantiomers was performed after Step 5 rather than in Step 4, using the chiral column Chiralpak IA and Mobile Phase 40% EtOH/hexanes-DCM (5:1) (0.1% Et₂NH). Stereochemistry of the separated enantiomers were arbitrarily assigned. ⁵Notes on procedures: In Step 4, the amide coupling reaction was performed with HBTU and Et₃N in DMA. Chiral separation of the enantiomers was performed after Step 5 rather than in Step 4, using the chiral column Chiralpak IG andMobile Phase 30% EtOH/MTBE (containing 8 mM NH₃ in MeOH). Stereochemistry of the separated enantiomers were arbitrarily assigned. ⁶Notes on procedures: In Step 4, the amide coupling reaction was performed with HBTU and Et₃N in DMA. The enantiomers were separated by chiral HPLC using the chiral column Chiralpak IC and Mobile Phase 15% EtOH/MTBE. Stereochemistry of the separated enantiomers were arbitrarily assigned. ⁷Notes on procedures: In Step 4, the amide coupling reaction was performed with HBTU and Et₃N in DMA. The enantiomers were separated by chiral HPLC using the chiral column Chiralpak IG and Mobile Phase 30% EtOH/MTBE. Stereochemistry of the separated enantiomers were arbitrarily assigned. ⁸Notes on procedures: In Step 4, the carboxylic acid Intermediate 24 was used. The amide coupling reaction was performed with HBTU and Et₃N in DMA. The enantiomers were separated by chiral HPLC using the chiral column Chiralpak IG and Mobile Phase 30% EtOH/MTBE. Stereochemistry of the separated enantiomers were arbitrarily assigned. ⁹Notes on procedures: In Step 2, cyanation was achieved in the presence of Zn (2 eq), Zn(CN)2 (10 eq), Pd(P(t-Bu)₃)₂ (0.5 eq), and 4,4′-di-tert-butyl-2,2′-bipyridine (1 eq) in DMA, with heating at 97° C. for 2 h. ¹⁰Notes on procedures: In Step 4, the amide coupling reaction was performed with HBTU and Et₃N in DMA. The enantiomers were separated by chiral HPLC using the chiral column Chiralpak ID-2 and Mobile Phase 15% EtOH/MTBE (0.1% Et₂NH). Stereochemistry of the separated enantiomers were arbitrarily assigned.

Example 15-1. (R)-3-Amino-6-methyl-N-(3-(piperazin-1-yl)-5,6,7,8-tetrahydroquinolin-7-yl)thieno[2,3-b]pyridine-2-carboxamide and Example 15-2. (S)-3-Amino-6-methyl-N-(3-(piperazin-1-yl)-5,6,7,8-tetrahydroquinolin-7-yl)thieno[2,3-b]pyridine-2-carboxamide (Stereoconfiguration Assumed)

Step 1. Benzyl (3-nitro-5,6,7,8-tetrahydroquinolin-7-yl)carbamate

A mixture of benzyl (3-oxocyclohexyl)carbamate (247 mg, 0.999 mmol) and 1-methyl-3,5-dinitropyridin-2(1H)-one (300 mg, 1.507 mmol) in ammonia/MeOH (1M, 6 mL) was microwaved at 90° C. for 30 min to provide a blackish-red solution. Eleven more samples of the same composition were run under the same conditions. The twelve samples were combined and evaporated under reduced pressure. The residue was partitioned between DCM (300 mL) and saturated aqueous NaHCO₃ (100 mL). The organic layer was washed with brine (100 mL), dried (MgSO₄), filtered, treated with silica gel, and evaporated under reduced pressure. Purification by silica gel chromatography (0 to 50% EtOAc in hexanes) provided a mixture of benzyl (3-nitro-5,6,7,8-tetrahydroquinolin-7-yl)carbamate and undesired regioisomer benzyl (3-nitro-5,6,7,8-tetrahydroquinolin-5-yl)carbamate as a pale yellow gum. The mixture was used without further purification. MS (ESI, m/z): 213 [M+H]⁺.

Step 2. Benzyl (3-amino-5,6,7,8-tetrahydroquinolin-7-yl)carbamate

A solution of benzyl (3-nitro-5,6,7,8-tetrahydroquinolin-7-yl)carbamate and regioisomer (2.64 g, 8.07 mmol) in ethanol (110 mL) was treated with tin(II) chloride dihydrate (9.10 g, 40.3 mmol) and conc. HCl (1 mL), then stirred at 80° C. for 75 min. The solution was allowed to cool, then was concentrated under reduced pressure to about 15 mL. The sample was made basic (pH ˜9) by addition of saturated aqueous NaHCO₃; about midway through, the sample was diluted with DCM (100 mL). The mixture was triturated, then filtered, and the filter cake was washed with DCM (50 mL). The filter cake was triturated and sonicated in MeOH (200 mL), then the mixture was filtered. The slightly cloudy filtrate was filtered through Celite 545, then concentrated to provide a yellow solid. Purification by silica gel chromatography (0 to 15% MeOH in DCM) provided a mixture of benzyl (3-amino-5,6,7,8-tetrahydroquinolin-7-yl)carbamate and regioisomer as a yellow solid. The mixture was used without further purification. MS (ESI, m/z): 298 [M+H]⁺.

Step 3. Benzyl (3-iodo-5,6,7,8-tetrahydroquinolin-7-yl)carbamate

A sample of benzyl (3-amino-5,6,7,8-tetrahydroquinolin-7-yl)carbamate and regioisomer (1.25 g, 4.22 mmol) was treated with ACN (17 mL). The material was cooled on a dry ice/ethylene glycol bath (approximately −10 to −15° C.) and PTSA monohydrate (1.61 g, 8.45 mmol) was added. After stirring 10 min, a solution of potassium iodide (1.05 g, 6.33 mmol) and sodium nitrite (0.436 g, 6.32 mmol) in water (3.4 mL) was added dropwise over 20 min. The dry ice bath was replaced with an ice bath, and the reddish-brown mixture was stirred at 0° C. for 3 h 40 min. The solution was diluted with EtOAc (50 mL), cooled on an ice bath and treated with saturated aqueous NaHCO₃ until basic (pH ˜8-9). The organic layer was removed and the aqueous layer was extracted once more with EtOAc (50 mL). The combined organics were washed sequentially with water and brine (50 mL each), dried (Na₂SO₄), filtered, treated with silica gel, and evaporated under reduced pressure. Purification by silica gel chromatography (0 to 23% EtOAc in hexanes) provided a mixture of benzyl (3-iodo-5,6,7,8-tetrahydroquinolin-7-yl)carbamate and regioisomer as a yellow solid. The mixture was used without further purification. MS (ESI, m/z): 409 [M+H]⁺.

Step 4. Tert-Butyl 4-(7-(((benzyloxy)carbonyl)amino)-5,6,7,8-tetrahydroquinolin-3-yl)piperazine-1-carboxylate

A mixture of t-BuXPhos Pd G4 (76.3 mg, 94.4 μmole), benzyl (3-iodo-5,6,7,8-tetrahydroquinolin-7-yl)carbamate and regioisomer (605.0 mg, 1.482 mmol), tert-butyl piperazine-1-carboxylate (553.5 mg, 2.97 mmol), and sodium tert-butoxide (257.1 mg, 2.68 mmol) was sealed in a 40-mL vial. The atmosphere was evacuated and replaced with nitrogen, three times. Dioxane (15 mL) was added and the solution was stirred at ambient temperature for three days. Material at the same stage from a previous run (from 40.7 mg, 0.100 mmol iodo starting material) was added. The mixture was diluted with EtOAc (˜100 mL), treated with silica gel, and evaporated under reduced pressure. Purification by silica gel chromatography (0 to 87% EtOAc in hexanes) provided a mixture of tert-butyl 4-(7-(((benzyloxy)carbonyl)amino)-5,6,7,8-tetrahydroquinolin-3-yl)piperazine-1-carboxylate and regioisomer as a yellow foam. The mixture was used without further purification. MS (ESI, m/z): 467 [M+H]⁺.

Step 5. Tert-Butyl 4-(7-amino-5,6,7,8-tetrahydroquinolin-3-yl)piperazine-1-carboxylate

A suspension of Pd/C (10%) (57.1 mg, 0.054 mmol) and the mixture of tert-butyl 4-(7-(((benzyloxy)carbonyl)amino)-5,6,7,8-tetrahydroquinolin-3-yl)piperazine-1-carboxylate and regioisomer (485 mg, 1.039 mmol) in MeOH (5 mL) was stirred at ambient temperature under an atmosphere of hydrogen overnight. The sample was filtered through Celite 545 under vacuum, and the Celite was rinsed with MeOH. The filtrate was evaporated to provide a mixture of tert-butyl 4-(7-amino-5,6,7,8-tetrahydroquinolin-3-yl)piperazine-1-carboxylate and regioisomer as an orange gum. The mixture was used without further purification. MS (ESI, m/z): 333 [M+H]⁺.

Step 6. Tert-Butyl 4-(7-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-5,6,7,8-tetrahydroquinolin-3-yl)piperazine-1-carboxylate

A solution of tert-butyl 4-(7-amino-5,6,7,8-tetrahydroquinolin-3-yl)piperazine-1-carboxylate and regioisomer (130 mg, 0.391 mmol) in DCM (6 ml) was treated with 3-amino-6-methylthieno[2,3-b]pyridine-2-carboxylic acid (74 mg, 0.355 mmol), BOP (188.4 mg, 0.426 mmol), and DIEA (186.4 μL, 1.067 mmol). The solution was stirred at ambient temperature for 4.5 h. The mixture was diluted with EtOAc (40 mL) and washed sequentially with 2M aqueous Na₂CO₃ (20 mL) and brine (2×40 mL). Heptane (˜15 mL) was added, then the mixture was evaporated under reduced pressure to dryness. Purification by silica gel chromatography (0 to 100% EtOAc in hexanes) provided a mixture of tert-butyl 4-(7-(3-amino-6-methylthieno[2,3-1)]pyridine-2-carboxamido)-5,6,7,8-tetrahydroquinolin-3-yl)piperazine-1-carboxylate and regioisomer as a yellow solid. MS (ESI, m/z): 523 [M+H]⁺.

Step 7. (R)-3-Amino-6-methyl-N-(3-(piperazin-1-yl)-5,6,7,8-tetrahydroquinolin-7-yl)thieno[2,3-b]pyridine-2-carboxamide and (S)-3-Amino-6-methyl-N-(3-(piperazin-1-yl)-5,6,7,8-tetrahydroquinolin-7-yl)thieno[2,3-b]pyridine-2-carboxamide

Regioisomer Purification:

A solution of the mixture of tert-butyl 4-(7-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-5,6,7,8-tetrahydroquinolin-3-yl)piperazine-1-carboxylate and regioisomer (97.3 mg, 0.186 mmol) in DCM (5 mL) and MeOH (1 mL) was treated with HCl (4 M in dioxane; 1.5 mL, 6.00 mmol), and allowed to stand at ambient temperature for 30 min; within 5 min a yellow precipitate began to form. The mixture was concentrated under reduced pressure. The residue was triturated in Et₂O (10 mL), then the solids were collected and washed with Et₂O (20 mL) to provide a mixture of 3-amino-6-methyl-N-(3-(piperazin-1-yl)-5,6,7,8-tetrahydroquinolin-7-yl)thieno[2,3-b]pyridine-2-carboxamide and regioisomer as a yellow solid. The material was purified by prep-HPLC (Column: Chiralpak IB, 250×4.6 mm, 5 μm; Mobile phase A: hexanes, B: Ethanol/Et₂NH; Gradient 60% B; Total Flow: 5 mL/min; Detector: 190 nm to 500 nm) to provided 3-amino-6-methyl-N-(3-(piperazin-1-yl)-5,6,7,8-tetrahydroquinolin-7-yl)thieno[2,3-b]pyridine-2-carboxamide as the major regioisomer peak which was then carried on to chiral separation.

Chiral Purification:

The crude product of 3-amino-6-methyl-N-[3-(piperazin-1-yl)-5,6,7,8-tetrahydroquinolin-7-yl]thieno[2,3-b]pyridine-2-carboxamide (20 mg, 0.04 mmol, 90%) was separated into its enantiomers by chiral HPLC (Column: Chiralpak IC, 2×25 cm, Sum; Mobile phase: hexanes, 0.1% Et₂NH and ethanol (hold 50% ethanol for 30 min)). The first eluting isomer (RT=23.0 min) was isolated as a pale yellow solid, stereochemistry arbitrarily assigned as (R)-3-amino-6-methyl-N-(3-(piperazin-1-yl)-5,6,7,8-tetrahydroquinolin-7-yl)thieno[2,3-b]pyridine-2-carboxamide. ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 8.30 (d, J=8.1 Hz, 1H), 8.06-8.05 (br s, 1H), 7.61 (d, J=7.5 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.16-7.15 (br s, 2H), 7.02 (d, J=2.4 Hz, 1H), 4.25-4.10 (m, 1H), 3.05-3.02 (m, 5H), 2.93-2.71 (m, 8H), 2.58 (s, 3H), 2.05-1.96 (m, 1H), 1.79-1.65 (m, 1H). MS: (ESI, m/z): 423 [M+H]⁺.

The second eluting isomer (RT=27.5 min) was isolated as a pale yellow solid, stereochemistry arbitrarily assigned as (S)-3-amino-6-methyl-N-(3-(piperazin-1-yl)-5,6,7,8-tetrahydroquinolin-7-yl)thieno[2,3-b]pyridine-2-carboxamide. ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 8.30 (d, J=8.1 Hz, 1H), 8.06-8.05 (br s, 1H), 7.61 (d, J=7.5 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.16-7.15 (br s, 2H), 7.02 (d, J=2.4 Hz, 1H), 4.25-4.10 (m, 1H), 3.05-3.02 (m, 5H), 2.93-2.71 (m, 8H), 2.58 (s, 3H), 2.05-1.96 (m, 1H), 1.79-1.65 (m, 1H). MS: (ESI, m/z): 423 [M+H]⁺.

Example 16. (R)-3-Amino-6-methyl-N-(7-(piperazin-1-yl)-3,4-dihydro-2H-pyrano[3,2-c]pyridin-3-yl)thieno[2,3-b]pyridine-2-carboxamide

Step 1. Tert-Butyl (R)-4-(3-(((benzyloxy)carbonyl)amino)-3,4-dihydro-2H-pyrano[3,2-c]pyridin-7-yl)piperazine-1-carboxylate

A solution of benzyl (R)-(7-chloro-3,4-dihydro-2H-pyrano[3,2-c]pyridin-3-yl)carbamate (Intermediate 42) (200 mg, 0.60 mmol), RuPhos (28 mg, 0.06 mmol), tert-butyl piperazine-1-carboxylate (175 mg, 0.94 mmol), RuPhos Pd G3 (50 mg, 0.06 mmol) and Cs₂CO₃ (410 mg, 1.26 mmol) in toluene (5 mL) was stirred for 16 h at 95° C. After cooling to 25° C., the reaction was then quenched by the addition of water (10 mL). The resulting mixture was extracted with DCM (3×10 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:2 ethyl acetate/pet. ether) to afford tert-butyl (R)-4-(3-(((benzyloxy)carbonyl)amino)-3,4-dihydro-2H-pyrano[3,2-c]pyridin-7-yl)piperazine-1-carboxylate as a white solid. MS: (ESI, m/z): 469 [M+H]⁺.

Step 2. Tert-Butyl (R)-4-(3-amino-3,4-dihydro-2H-pyrano[3,2-c]pyridin-7-yl)piperazine-1-carboxylate

A mixture of tert-butyl (R)-4-(3-(((benzyloxy)carbonyl)amino)-3,4-dihydro-2H-pyrano[3,2-c]pyridin-7-yl)piperazine-1-carboxylate (100 mg, 0.20 mmol) and Palladium on carbon (20 mg, 10%) in ethyl acetate (10 mL) was stirred for 2 h at 25° C. under an atm of hydrogen. The solid was filtered out and the cake was washed with methanol (3×10 mL). The filtrate was concentrated under vacuum to give tert-butyl (R)-4-(3-amino-3,4-dihydro-2H-pyrano[3,2-c]pyridin-7-yl)piperazine-1-carboxylate as a white solid. MS: (ESI, m/z): 335 [M+H]⁺.

Step 3. Tert-Butyl (R)-4-(3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-3,4-dihydro-2H-pyrano[3,2-c]pyridin-7-yl)piperazine-1-carboxylate

A solution of tert-butyl 4-[(3R)-3-amino-2H,3H,4H-pyrano[3,2-c]pyridin-7-yl]piperazine-1-carboxylate (65 mg, 0.18 mmol), HBTU (108 mg, 0.28 mmol), Et₃N (85 mg, 0.84 mmol) and 3-amino-6-methylthieno[2,3-b]pyridine-2-carboxylic acid (49 mg, 0.22 mmol) in DMA (3 mL) was stirred for 30 min at 25° C. The reaction was then quenched by the addition of water (10 mL). The resulting mixture was extracted with DCM (2×10 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:1 ethyl acetate/pet. ether) to afford tert-butyl (R)-4-(3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-3,4-dihydro-2H-pyrano[3,2-c]pyridin-7-yl)piperazine-1-carboxylate as a colorless oil. MS: (ESI, m/z): 525 [M+H]⁺.

Step 4. (R)-3-Amino-6-methyl-N-(7-(piperazin-1-yl)-3,4-dihydro-2H-pyrano[3,2-c]pyridin-3-yl)thieno[2,3-b]pyridine-2-carboxamide

A solution of tert-butyl (R)-4-(3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-3,4-dihydro-2H-pyrano[3,2-c]pyridin-7-yl)piperazine-1-carboxylate (45 mg, 0.08 mmol) and TFA (1 mL) in DCM (3 mL) was stirred for 30 min at 25° C. and concentrated under vacuum. The residue was purified by prep-HPLC (Column: X Bridge C18, 19×150 mm, 5 μm; Mobile Phase A: water (10 mM NH₄HCO₃), B: ACN; Gradient: 10% B to 80% B over 10 min) to afford (R)-3-amino-6-methyl-N-(7-(piperazin-1-yl)-3,4-dihydro-2H-pyrano[3,2-c]pyridin-3-yl)thieno[2,3-b]pyridine-2-carboxamide as a white solid. ¹H NMR (DMSO-d₆, 300 MHz) δ (ppm): 8.33 (d, J=8.4 Hz, 1H), 7.83 (s, 1H), 7.59 (br s, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.23 (br s, 2H), 6.14 (s, 1H), 4.27-4.20 (m, 2H), 3.92-3.86 (m, 1H), 3.48-3.35 (m, 1H), 3.33-3.22 (m, 4H), 2.84-2.81 (m, 2H), 2.76-2.72 (m, 4H), 2.58 (s, 3H). MS: (ESI, m/z): 425 [M+H]⁺.

Example 17. N-((3R)-7-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3,4-dihydro-2H-pyrano[3,2-c]pyridin-3-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide

Step 1. Benzyl (R)-benzyl(7-chloro-3,4-dihydro-2H-pyrano[3,2-c]pyridin-3-yl)carbamate

A solution of benzyl (R)-(7-chloro-3,4-dihydro-2H-pyrano[3,2-c]pyridin-3-yl)carbamate (Intermediate 42) (250 mg, 0.75 mmol), sodium hydride (63 mg, 1.58 mmol, 60%) and benzyl bromide (268 mg, 1.57 mmol) in DMF (5 mL) was stirred for 2 h at 25° C. The reaction was then quenched by the addition of 15 mL of water. The resulting mixture was extracted with 3×15 mL of ethyl acetate and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:3 ethyl acetate/pet. ether) to give benzyl (R)-benzyl(7-chloro-3,4-dihydro-2H-pyrano[3,2-c]pyridin-3-yl)carbamate as a light yellow solid. MS: (ESI, m/z): 409, 411 [M+H]⁺.

Step 2. (R)-3-(Benzyl((benzyloxy)carbonyl)amino)-7-chloro-3,4-dihydro-2H-pyrano[3,2-c]pyridine 6-oxide

A solution of benzyl (R)-benzyl(7-chloro-3,4-dihydro-2H-pyrano[3,2-c]pyridin-3-yl)carbamate (300 mg, 0.70 mmol) and m-CPBA (633 mg, 3.67 mmol) in DCM (10 mL) was stirred for 16 h at 25° C. The reaction was then quenched by the addition of 10 mL of Na₂S₂O₃ (sat.) and 10 mL of NaHCO₃ (sat.). The resulting mixture was extracted with 3×20 mL of DCM and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 10:1 DCM/methanol) to give (R)-3-(benzyl((benzyloxy)carbonyl)amino)-7-chloro-3,4-dihydro-2H-pyrano[3,2-c]pyridine 6-oxide as a light yellow solid. MS: (ESI, m/z): 425, 427 [M+H]⁺.

Step 3. (3R)-3-(Benzyl((benzyloxy)carbonyl)amino)-7-(8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3,4-dihydro-2H-pyrano[3,2-c]pyridine 6-oxide

A solution of (R)-3-(benzyl((benzyloxy)carbonyl)amino)-7-chloro-3,4-dihydro-2H-pyrano[3,2-c]pyridine 6-oxide (498 mg, 2.35 mmol) and diisopropylethylamine (303 mg, 2.34 mmol) in tert-butanol (8 mL) was stirred for 16 h at 90° C. After cooling to 25° C., the resulting mixture was concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 10:1 DCM/methanol) to give (3R)-3-(benzyl((benzyloxy)carbonyl)amino)-7-(8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3,4-dihydro-2H-pyrano[3,2-c]pyridine 6-oxide as a yellow solid. MS: (ESI, m/z): 601 [M+H]⁺.

Step 4. (3R)-3-(Benzyl((benzyloxy)carbonyl)amino)-7-(8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3,4-dihydro-2H-pyrano[3,2-c]pyridine 6-oxide

To a solution of (3R)-3-(benzyl((benzyloxy)carbonyl)amino)-7-(8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3,4-dihydro-2H-pyrano[3,2-c]pyridine 6-oxide (100 mg, 0.16 mmol) in DCM (10 mL) and a solution of trimethylamine in THF (1M, 0.83 mL, 0.83 mmol) was added TFAA (105 mg, 0.50 mmol) at 0° C. The resulting solution was stirred for 1 h at 25° C. and concentrated under vacuum. The residue was purified by silica gel column (eluting with 5:1 DCM/methanol) to give the intermediate (crude): ((3R)-3-(benzyl((benzyloxy)carbonyl)amino)-7-(8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N,N,N-trimethyl-3,4-dihydro-2H-pyrano[3,2-c]pyridin-5-aminium). The intermediate was dissolved in DMF (4 mL). TBAF (83 mg, 0.32 mmol) was added. The resulting solution was stirred for 30 min at 90° C. After cooling to 25° C., the reaction was then quenched by the addition of 10 mL of water. The resulting mixture was extracted with 3×10 mL of ethyl acetate and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:2 ethyl acetate/pet. ether) to give (3R)-3-(benzyl((benzyloxy)carbonyl)amino)-7-(8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3,4-dihydro-2H-pyrano[3,2-c]pyridine 6-oxide as a yellow solid. MS: (ESI, m/z): 619 [M+H]⁺.

Step 5. Tert-Butyl 3-((R)-3-amino-5-fluoro-3,4-dihydro-2H-pyrano[3,2-c]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

A mixture of (3R)-3-(benzyl((benzyloxy)carbonyl)amino)-7-(8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3,4-dihydro-2H-pyrano[3,2-c]pyridine 6-oxide (58 mg, 0.09 mmol) and palladium on carbon (50 mg, 5%) in ethyl acetate (5 mL) was stirred for 2 h at 25° C. under hydrogen atmosphere. The solids were filtered out. The filtrate was concentrated under vacuum to give tert-butyl 3-((R)-3-amino-5-fluoro-3,4-dihydro-2H-pyrano[3,2-c]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a light yellow solid. MS: (ESI, m/z): 379 [M+H]⁺.

Step 6. Tert-Butyl 3-((R)-3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-5-fluoro-3,4-dihydro-2H-pyrano[3,2-c]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

A solution of tert-butyl 3-((R)-3-amino-5-fluoro-3,4-dihydro-2H-pyrano[3,2-c]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (35 mg, 0.09 mmol), 3-amino-6-methylthieno[2,3-b]pyridine-2-carboxylic acid (21 mg, 0.10 mmol), HBTU (57 mg, 0.15 mmol) and Et₃N (30 mg, 0.30 mmol) in DMA (3 mL) was stirred for 1 h at 25° C. The reaction was then quenched by the addition of 10 mL of water. The resulting mixture was extracted with 3×15 mL of ethyl acetate and the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:2 ethyl acetate/pet. ether) to give tert-butyl 3-((R)-3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-5-fluoro-3,4-dihydro-2H-pyrano[3,2-c]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. MS: (ESI, m/z): 569 [M+H]⁺.

Step 7. N-((3R)-7-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3,4-dihydro-2H-pyrano[3,2-c]pyridin-3-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide

A solution of tert-butyl 3-((R)-3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-5-fluoro-3,4-dihydro-2H-pyrano[3,2-c]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (25 mg, 0.04 mmol) and TFA (1 mL) in DCM (3 mL) was stirred for 1 h at 25° C. The resulting mixture was concentrated under vacuum. The residue was purified by prep-HPLC (Column:) (Bridge Shield RP18 OBD, 30×150 mm, 5 μm; Mobile phase A: Water (10 mM NH₄HCO₃), B: ACN; Gradient: 20% B to 47% B within 7 min). The collected fraction was concentrated under vacuum to give N-((3R)-7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3,4-dihydro-2H-pyrano[3,2-c]pyridin-3-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide as an off-white solid. ¹H NMR (DMSO-d₆, 300 MHz) δ (ppm): 8.33 (d, J=8.4 Hz, 1H), 7.62 (br s, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.23 (s, 2H), 5.92 (s, 1H), 4.28-4.19 (m, 2H), 3.99-3.93 (m, 1H), 3.63-3.59 (m, 2H), 3.47-3.45 (m, 2H), 2.79-2.65 (m, 5H), 2.58 (s, 3H), 1.65-1.53 (m, 4H). MS: (ESI, m/z): 469 [M+H]⁺.

Example 18. N-((3R)-7-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-3,4-dihydro-2H-pyrano[3,2-c]pyridin-3-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide

Step 1. Tert-Butyl 3-((R)-3-(((benzyloxy)carbonyl)amino)-3,4-dihydro-2H-pyrano[3,2-c]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

A solution of benzyl (R)-(7-chloro-3,4-dihydro-2H-pyrano[3,2-c]pyridin-3-yl)carbamate (Intermediate 42) (500 mg, 1.57 mmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (401 mg, 1.89 mol), RuPhos (88 mg, 0.19 mmol), RuPhos Pd G3 (129 mg, 0.15 mmol) and Cs₂CO₃ (1.03 g, 3.16 mmol) in toluene (20 mL) was stirred overnight at 95° C. After cooling to 24° C., the solids were filtered out and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:1 ethyl acetate/pet. ether) to give tert-butyl 3-((R)-3-(((benzyloxy)carbonyl)amino)-3,4-dihydro-2H-pyrano[3,2-c]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a white solid. MS: (ESI, m/z): 495 [M+H]⁺.

Step 2. Tert-Butyl 3-((R)-3-(((benzyloxy)carbonyl)amino)-8-fluoro-3,4-dihydro-2H-pyrano[3,2-c]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

To a solution of tert-butyl 3-((R)-3-(((benzyloxy)carbonyl)amino)-3,4-dihydro-2H-pyrano[3,2-c]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 1.01 mmol) in DCM (25 mL) and methanol (25 mL) was added a solution of Selectfluor (358 mg, 1.01 mmol) in ACN (25 mL) at −10° C. The resulting solution was stirred 2 h at −10° C. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase chromatography (Column: C₁₈ silica gel; Mobile phase A: water (0.1% TFA), B: ACN; Flow rate: 50 mL/min; Gradient: 0% B to 80% B within 30 min). The collected fractions were concentrated under vacuum to give tert-butyl 3-((R)-3-(((benzyloxy)carbonyl)amino)-8-fluoro-3,4-dihydro-2H-pyrano[3,2-c]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow oil. MS: (ESI, m/z): 513 [M+H]⁺.

Step 3. Tert-Butyl 3-((R)-3-amino-8-fluoro-3,4-dihydro-2H-pyrano[3,2-c]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

A suspension of tert-butyl 3-((R)-3-(((benzyloxy)carbonyl)amino)-8-fluoro-3,4-dihydro-2H-pyrano[3,2-c]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.20 mmol) and Palladium on carbon (20 mg, 10%) in ethyl acetate (5 mL) was stirred for 1.5 h at 24° C. under hydrogen atmosphere. The solids were filtered out. The filtrate was concentrated under vacuum to afford tert-butyl 3-((R)-3-amino-8-fluoro-3,4-dihydro-2H-pyrano[3,2-c]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow oil. MS: (ESI, m/z): 379 [M+H]⁺.

Step 4. Tert-Butyl 3-((R)-3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-8-fluoro-3,4-dihydro-2H-pyrano[3,2-c]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

A solution of tert-butyl 3-((R)-3-amino-8-fluoro-3,4-dihydro-2H-pyrano[3,2-c]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (80 mg, 0.13 mmol, purity 60%), 3-amino-6-methylthieno[2,3-b]pyridine-2-carboxylic acid (47 mg, 0.23 mmol), Et₃N (64 mg, 0.63 mmol) and HBTU (96 mg, 0.25 mmol) in DMA (3 mL) was stirred for 30 min at 24° C. The resulting solution was purified by reverse phase chromatography (Column: C₁₈ silica gel; Mobile phase A: water (10 mM NH₄HCO₃), B: ACN; Flow rate: 50 mL/min; Gradient: 0% B increasing to 75% B within 30 min). The collected fraction was concentrated under vacuum and to give tert-butyl 3-((R)-3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-8-fluoro-3,4-dihydro-2H-pyrano[3,2-c]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow solid. MS: (ESI, m/z): 569 [M+H]⁺.

Step 5. N-((3R)-7-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-3,4-dihydro-2H-pyrano[3,2-c]pyridin-3-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide

A solution of tert-butyl 3-((R)-3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-8-fluoro-3,4-dihydro-2H-pyrano[3,2-c]pyridin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40 mg, 0.07 mmol) and TFA (1 mL) in DCM (3 mL) was stirred for 1 h at 24° C. The resulting mixture was concentrated under vacuum. The mixture was purified by prep-HPLC (Column:) (Bridge Shield RP18 OBD, 5 μm, 19×150 mm; Mobile phase A: water (10 mM NH₄HCO₃), B: ACN; Gradient: 10% B to 40% B within 2 min, increasing to 60% in 7 min)). The collected fraction was lyophilized to give N-((3R)-7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-3,4-dihydro-2H-pyrano[3,2-c]pyridin-3-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide as a light yellow solid. ¹H NMR (DMSO-d₆, 300 MHz) δ (ppm): 8.33 (d, J=8.1 Hz, 1H), 7.69 (s, 1H), 7.65 (br s, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.23 (br s, 2H), 4.32-7.29 (m, 2H), 4.05-3.95 (m, 1H), 3.60-3.48 (m, 2H), 3.48-3.40 (m, 2H), 2.97-2.91 (m, 4H), 2.58 (s, 3H), 1.72-1.68 (m, 4H). MS: (ESI, m/z): 469 [M+H]⁺.

Example 19. (R)-3-Amino-6-methyl-N-(7-(piperazin-1-yl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-3-yl)thieno[2,3-b]pyridine-2-carboxamide

Step 1. Tert-Butyl (R)-4-(3-(((benzyloxy)carbonyl)amino)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-7-yl)piperazine-1-carboxylate

A solution of benzyl (R)-(7-chloro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-3-yl)carbamate (Intermediate 43) (200 mg, 0.56 mmol), tert-butyl piperazine-1-carboxylate (140 mg, 0.75 mmol), RuPhos Pd G3 (52 mg, 0.06 mmol), RuPhos (59 mg, 0.13 mmol) and Cs₂CO₃ (618 mg, 1.90 mmol) in toluene (5 mL) was stirred for 3 h at 100° C. After cooling to 25° C., the reaction was then quenched by the addition of 10 mL of water. The resulting mixture was extracted with 3×10 mL of ethyl acetate and the organic layers combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:3 ethyl acetate/pet. ether) to give tert-butyl (R)-4-(3-(((benzyloxy)carbonyl)amino)-3,4-dihydro-2H-pyrano[2,3]pyridin-7-yl)piperazine-1-carboxylate as an off-white solid. MS: (ESI, m/z): 469 [M+H]⁺.

Step 2. Tert-Butyl (R)-4-(3-amino-3,4-dihydro-2H-pyrano[2,3-b]pyridin-7-yl)piperazine-1-carboxylate

A suspension of tert-butyl (R)-4-(3-(((benzyloxy)carbonyl)amino)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-7-yl)piperazine-1-carboxylate (270 mg, 0.52 mmol) and Palladium on carbon (30 mg, 10%) in ethyl acetate (20 mL) was stirred for 4 h at 25° C. The solids were filtered out. The filtrate was concentrated under vacuum to tert-butyl (R)-4-(3-amino-3,4-dihydro-2H-pyrano[2,3-b]pyridin-7-yl)piperazine-1-carboxylate as a brown oil. MS: (ESI, m/z): 335 [M+H]⁺.

Step 3. Tert-Butyl (R)-4-(3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-7-yl)piperazine-1-carboxylate

A solution of tert-butyl (R)-4-(3-amino-3,4-dihydro-2H-pyrano[2,3-b]pyridin-7-yl)piperazine-1-carboxylate (50 mg, 0.13 mmol), 3-amino-6-methylthieno[2,3-b]pyridine-2-carboxylic acid (34 mg, 0.16 mmol), HBTU (62 mg, 0.16 mmol) and Et₃N (45 mg, 0.44 mmol) in DMA (3 mL) was stirred for 30 min at 25° C. The reaction was then quenched by the addition of 10 mL of water. The resulting mixture was extracted with 3×10 mL of ethyl acetate. The organic layers combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by reverse phase chromatography (Column: C₁₈ silica gel; Mobile phase A: water (0.1% formic acid), B: ACN; Flow rate: 50 mL/min; Gradient: 0% increasing to 100% B within 40 min). The collected fraction was concentrated under vacuum. The collected fraction was concentrated under vacuum to give tert-butyl (R)-4-(3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-7-yl)piperazine-1-carboxylate as a yellow solid. MS: (ESI, m/z): 525 [M+H]⁺.

Step 4. (R)-3-Amino-6-methyl-N-(7-(piperazin-1-yl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-3-yl)thieno[2,3-b]pyridine-2-carboxamide

A solution of tert-butyl (R)-4-(3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-7-yl)piperazine-1-carboxylate (30 mg, 0.05 mmol) and TFA (1 mL) in DCM (3 mL) was stirred for 30 min at 25° C. The resulting mixture was concentrated under vacuum. The residue was purified by prep-HPLC (Column: XBridge Shield RP18 OBD, 19×250 mm, 10 μm; Mobile phase A: Water (10 mM NH₄HCO₃), B: ACN; Gradient: 20% B to 38% B in 8 min). The collected fraction was lyophilized to give (R)-3-amino-6-methyl-N-(7-(piperazin-1-yl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-3-yl)thieno[2,3-b]pyridine-2-carboxamide as an off-white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.33 (d, J=8.4 Hz, 1H), 7.55 (br s, 1H), 7.32-7.27 (m, 2H), 7.22 (br s, 2H), 6.37 (d, J=8.4 Hz, 1H), 4.33-4.20 (m, 2H), 3.99-3.94 (m, 1H), 3.49-3.31 (m, 5H), 2.89-2.74 (m, 6H), 2.59 (s, 3H). MS: (ESI, m/z): 425 [M+H]⁺.

Example 20. (R)-3-Amino-N-(6-fluoro-7-(piperazin-1-yl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide

Step 1. Tert-Butyl (R)-4-(3-(((benzyloxy)carbonyl)amino)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-7-yl)piperazine-1-carboxylate

A solution of benzyl (R)-(7-chloro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-3-yl)carbamate (Intermediate 43) (500 mg, 1.57 mmol), tert-butyl piperazine-1-carboxylate (352 mg, 1.19 mol), RuPhos Pd G3 (131 mg, 0.16 mmol), Ruphos (146 mg, 0.31 mmol) and Cs₂CO₃ (1.54 g, 4.72 mmol) in toluene (10 mL) was stirred for 3 h at 100° C. After cooling to 25° C., the reaction was quenched by the addition of 50 mL of water. Thre batches were thus run in parallel and combined for extraction work-up with ethyl acetate (3×50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:3 ethyl acetate/pet. ether) to afford tert-butyl (R)-4-(3-(((benzyloxy)carbonyl)amino)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-7-yl)piperazine-1-carboxylate as a yellow solid. MS: (ESI, m/z): 469 [M+H]⁺.

Step 2. Tert-Butyl (R)-4-(3-(((benzyloxy)carbonyl)amino)-6-fluoro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-7-yl)piperazine-1-carboxylate

To a solution of tert-butyl (R)-4-(3-(((benzyloxy)carbonyl)amino)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-7-yl)piperazine-1-carboxylate (580 mg, 1.24 mmol) in DCM (25 mL) and MeOH (25 mL) was added Selectfluor (441 mg, 1.24 mmol) at −20° C. The resulting mixture was stirred for 2 h at 25° C. The solvent was removed under vacuum. The residue was diluted with water (30 mL). The resulting mixture was extracted with DCM (3×30 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:10-1:3 ethyl acetate/pet. ether) to afford tert-butyl (R)-4-(3-(((benzyloxy)carbonyl)amino)-6-fluoro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-7-yl)piperazine-1-carboxylate as an off-white solid. MS: (ESI, m/z): 487 [M+H]⁺.

Step 3. Tert-Butyl (R)-4-(3-amino-6-fluoro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-7-yl)piperazine-1-carboxylate

A suspension of tert-butyl (R)-4-(3-(((benzyloxy)carbonyl)amino)-6-fluoro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-7-yl)piperazine-1-carboxylate (150 mg, 0.31 mmol) and Palladium on carbon (20 mg, 10%) in ethyl acetate (5 mL) was stirred for 2 h at 25° C. under hydrogen atmosphere. The solids were filtered out. The filtrate was concentrated under vacuum to give tert-butyl (R)-4-(3-amino-6-fluoro-3,4-dihydro-2H-pyrano[2,3]pyridin-7-yl)piperazine-1-carboxylate as a yellow oil. MS: (ESI, m/z): 353 [M+H]⁺.

Step 4. Tert-Butyl (R)-4-(3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-6-fluoro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-7-yl)piperazine-1-carboxylate

A solution of tert-butyl (R)-4-(3-amino-6-fluoro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-7-yl)piperazine-1-carboxylate (90 mg, 190 mmol), 3-amino-6-methylthieno[2,3-b]pyridine-2-carboxylic acid (56.0 mg, 270 mmol), HBTU (107 mg, 0.28 mmol) and Et₃N (77 mg, 0.76 mmol) in DMA (4 mL) was stirred for 1 h at 25° C. The reaction was quenched with water (10 mL). The resulting mixture was extracted with ethyl acetate (3×10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by reverse phase chromatography (Column: C₁₈ silica gel; Mobile phase A: water (0.1% TFA), B: ACN; Flow rate: 50 mL/min; Gradient: 0% B to 70% B within 40 min). The collected fractions were concentrated under vacuum to afford tert-butyl (R)-4-(3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-6-fluoro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-7-yl)piperazine-1-carboxylate as a yellow solid. MS: (ESI, m/z): 543 [M+H]⁺.

Step 5. (R)-3-Amino-N-(6-fluoro-7-(piperazin-1-yl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide

A solution of tert-butyl (R)-4-(3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-6-fluoro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-7-yl)piperazine-1-carboxylate (100 mg, 0.18 mmol) and TFA (1 mL) in DCM (3 mL) was stirred for 30 min at 25° C. The resulting mixture was concentrated under vacuum. A solution of NH₃ in methanol (7M) (5 mL) was added. The resulting mixture was stirred for 30 min at 25° C. The resulting mixture was concentrated under vacuum. The residue was purified by prep-HPLC (Column: XBridge Prep OBD C18, 30×150 mm 5 μm; Mobile Phase A: Water (10 mM NH₄HCO₃), B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 45% B in 7 min) to afford (R)-3-amino-N-(6-fluoro-7-(piperazin-1-yl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide as an off-white solid. ¹H NMR (DMSO-d₆, 300 MHz) δ (ppm): 8.32 (d, J=8.1 Hz, 1H), 7.59 (br s, 1H), 7.36-7.30 (m, 2H), 7.21 (br s, 2H), 4.33-4.19 (m, 2H), 4.01-3.95 (m, 1H), 3.23-3.20 (m, 4H), 2.89-2.73 (m, 6H), 2.58 (s, 3H). MS: (ESI, m/z): 443 [M+H]⁺.

Example 21-1. N-((2R)-6-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide

Step 1. Mixture of tert-butyl 3-(6-(((benzyloxy)carbonyl)amino)-3-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and tert-butyl 3-(6-(((benzyloxy)carbonyl)amino)-1-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

A solution of tert-butyl 3-(6-(((benzyloxy)carbonyl)amino)-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (800 mg, 1.63 mmol) and Selectfluor (634 mg, 1.79 mmol) in ACN (16 mL) was stirred for 18 h at 20° C. The reaction was quenched by the addition of 30 mL of water. The resulting mixture was extracted with 3×10 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1%-50% EtOAC/pet. ether) to afford a mixture of the regioisomers tert-butyl 3-(6-(((benzyloxy)carbonyl)amino)-3-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and tert-butyl 3-(6-(((benzyloxy)carbonyl)amino)-1-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a yellow oil. MS: (ESI, m/z): 510 [M+H]⁺.

Step 2. Mixture of tert-butyl 3-(6-amino-3-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and tert-butyl 3-(6-amino-1-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

A slurry of the mixture of tert-butyl 3-(6-[[(benzyloxy)carbonyl]amino]-3-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and tert-butyl 3-(6-[[(benzyloxy)carbonyl]amino]-1-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (508 mg, 1.00 mmol), and palladium on carbon (100 mg, 10%) in ethyl acetate (100 mL) was stirred for 1 h at 20° C. under a hydrogen atmosphere. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1%-50% MeOH/DCM) to afford a mixture of the regioisomers tert-butyl 3-(6-amino-3-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and tert-butyl 3-(6-amino-1-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a white solid. MS: (ESI, m/z): 376 [M+H]⁺.

Step 3. Mixture of tert-butyl 3-(6-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-1-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and tert-butyl 3-(6-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-3-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

A solution of the mixture of tert-butyl 3-(6-amino-1-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and tert-butyl 3-(6-amino-3-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 0.40 mmol), 3-amino-6-methylthieno[2,3-b]pyridine-2-carboxylic acid (99 mg, 479.45 mmol), EDCI (92 mg, 0.48 mmol), HOBt (65 mg, 0.48 mmol), and DIEA (155 mg, 1.20 mmol) in DMF (5 mL) was stirred for 2 h at 20° C. The reaction was quenched by the addition of 20 mL of water. The solids were collected by filtration and the crude product was purified by prep-HPLC (Column: XBridge BEH C18 OBD, 130 Å, 5 μm, 19×150 mm; Mobile phase A: water (10 mM NH₄HCO₃), B: ACN (60% ACN to 80% over 7 min)) to afford a mixture of the titled compounds.

Chiral separation. The mixture of regioisomers and enantiomers were partially separated by chiral HPLC (Column: Chiralpak IA, 250×20 mm, 5 um; Flow: 15 mL/min; Mobile Phase 10% MeOH/MTBE; Wavelength: from 190 nm to 500 nm) to afford a mixture of tert-butyl 3-((R)-6-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-1-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and tert-butyl 3-((R)-6-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-3-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Peak 1: RT=7.37 min; stereochemistry arbitrarily assigned); tert-butyl 3-((S)-6-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-1-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a white solid (Peak 2: RT=7.69 min; stereochemistry arbitrarily assigned); and tert-butyl 3-((S)-6-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-3-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a white solid (Peak 3: RT=13.70 min; stereochemistry arbitrarily assigned).

Peak 1 was further purified by chiral HPLC (Column: Phenomenex Lux 5u Cellulose-4, AXIA Packed, 250×21.5 mm, 5 um; Flow: 18 mL/min, Mobile Phase: MeOH; Wavelength: from 190 nm to 500 nm) to afford tert-butyl 3-((R)-6-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-1-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a white solid (RT=13.56 min; stereochemistry arbitrarily assigned), and tert-butyl 3-((R)-6-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-3-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a white solid (RT=17.31 min; stereochemistry arbitrarily assigned). MS for all 4 isomers: (ESI, m/z): 566 [M+H]⁺.

Step 4. N-((2R)-6-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide

A solution of tert-butyl 3-((R)-6-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-3-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (25 mg, 0.04 mmol) and TFA (1 mL) in DCM (5 mL) was stirred for 1 h at 20° C. The resulting mixture was concentrated under vacuum. The residue was diluted with 5 mL of DCM. The pH of the solution was adjusted to 8 with NH₃.in MeOH (7 M). The resulting mixture was concentrated under vacuum. The residue was purified by prep-HPLC (Column: XBridge Prep C18 OBD, 130 Å, 5 μm, 19×150 mm; Mobile phase: water (10 mM NH₄HCO₃), ACN (25% ACN up to 55% over 7 min)) to afford N-((2R)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide as an off-white solid. ¹H NMR (Methanol-d₄, 400 MHz) δ (ppm): 8.20 (d, J=8.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 6.80-6.76 (m, 2H), 4.25-4.17 (m, 1H), 3.53-3.51 (m, 2H), 3.16-3.14 (m, 2H), 3.10-2.99 (m, 2H), 2.92-2.90 (m, 2H), 2.82-2.74 (m, 2H), 2.64 (s, 3H), 2.18-2.12 (m, 1H), 2.04-2.02 (m, 2H), 1.87-1.82 (m, 3H). MS: (ESI, m/z): 466 [M+H]⁺.

The first three examples in Table 19 were prepared from the remaining three isomers isolated in Step 3 using standard chemical manipulations and procedures similar to those used for the preparation of Example 21-1. The rest of the examples in Table 19 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Examples 21-1 thru 21-4.

TABLE 19 LRMS Example m/z Number Structure and Compound Name [M + H]⁺ ¹H NMR 21-2

N-((2S)-6-(3,8- diazabicyclo[3.2.1]octan-3-yl)-5- fluoro-1,2,3,4-tetrahydronaphthalen- 2-yl)-3-amino-6-methylthieno[2,3- b]pyridine-2-carboxamide 466 (CD₃OD, 400 MHz) δ (ppm): 8.20 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 6.84-6.75 (m, 2H), 4.25-4.16 (m, 1H), 3.66-3.62 (s, 2H), 3.21-3.18 (m, 2H), 3.05-2.95 (m, 4H), 2.82-2.75 (m, 2H), 2.64 (s, 3H), 2.18-2.07 (m, 3H), 1.91-1.81 (m, 2H), 1.81-1.76 (m, 1H). 21-3

N-((2R)-6-(3,8- diazabicyclo[3.2.1]octan-3-yl)-7- fluoro-1,2,3,4-tetrahydronaphthalen- 2-yl)-3-amino-6-methylthieno[2,3- b]pyridine-2-carboxamide 466 (CD₃OD, 400 MHz) δ (ppm): 8.19 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 6.75-6.65 (m, 2H), 4.22-4.20 (m, 1H), 3.52-3.49 (m, 2H), 3.16-3.13 (m, 2H), 3.03-2.70 (m, 6H), 2.64 (s, 3H), 2.14-1.96 (m, 3H), 1.88-1.73 (m, 3H). 21-4

N-((2S)-6-(3,8- diazabicyclo[3.2.1]octan-3-yl)-7- fluoro-1,2,3,4-tetrahydronaphthalen- 2-yl)-3-amino-6-methylthieno[2,3- b]pyridine-2-carboxamide 466 (CD₃OD, 400 MHz) δ (ppm): 8.19 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 6.78-6.67 (m, 2H), 4.25-4.17 (m, 1H), 3.67-3.63 (m, 2H), 3.21-3.18 (m, 2H), 3.03-2.72 (m, 6H), 2.64 (s, 3H), 2.11-2.05 (m, 3H), 1.90-1.79 (m, 3H). 21-5¹

(R)-3-amino-N-(5-fluoro-6- (piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 440 (CD₃OD, 400 MHz) δ (ppm): 8.19 (d, J = 8.3 Hz, 1H), 7.38-7.29 (m, 1H), 6.94-6.78 (m, 2H), 4.32-4.19 (m, 1H), 3.09-2.94 (m, 10H), 2.85-2.70 (m, 2H), 2.64 (s, 3H), 2.25-2.13 (m, 1H), 1.82-1.75 (m, 1H). 21-6¹

(S)-3-amino-N-(5-fluoro-6- (piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 440 (CD₃OD, 400 MHz) δ (ppm): 8.19 (d, J = 8.3 Hz, 1H), 7.35-7.28 (m, 1H), 6.90-6.80 (m, 2H), 4.33-4.19 (m, 1H), 3.00 (s, 10H), 2.85-2.70 (m, 2H), 2.64 (s, 3H), 2.19-2.08 (m, 1H), 1.83-1.75 (m, 1H). 21-7¹

(R)-3-amino-N-(7-fluoro-6- (piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 440 (CD₃OD, 400 MHz) δ (ppm): 8.19 (d, J = 8.3 Hz, 1H), 7.35-7.28 (m, 1H), 6.82-6.73 (m, 2H), 4.29-4.18 (m, 1H), 3.04-2.93 (m, 9H), 2.94-2.85 (m, 2H), 2.85-2.67 (m, 1H), 2.64 (s, 3H), 2.18- 2.09 (m, 1H), 1.88-1.74 (m, 1H). 21-8¹

(S)-3-amino-N-(7-fluoro-6- (piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 440 (CD₃OD, 400 MHz) δ (ppm): 8.19 (d, J = 8.3 Hz, 1H), 7.35-7.28 (m, 1H), 6.90-6.80 (m, 2H), 4.33-4.19 (m, 1H), 3.00 (s, 10H), 2.85-2.70 (m, 2H), 2.64 (s, 3H), 2.19-2.08 (m, 1H), 1.83-1.75 (m, 1H). 21-9²

(R)-7-amino-N-(5-fluoro-6- (piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-3- methylthieno[2,3-b]pyrazine-6- carboxamide 441 (DMSO-d₆, 400 MHz) δ (ppm): 8.64 (s, 1H), 7.81 (d, J = 7.7 Hz, 1H), 6.78-6.94 (m, 3H), 6.71 (d, J = 9.0 Hz, 1H), 4.12 (s, 1H), 2.6-2.96 (m, 16H), 1.98 (d, J = 12.1 Hz, 1H), 1.67-1.82 (m, 1H). 21-10²

(S)-7-amino-N-(5-fluoro-6- (piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-3- methylthieno[2,3-b]pyrazine-6- carboxamide 441 (DMSO-d₆, 400 MHz) δ (ppm): 8.63 (s, 1H), 7.82 (d, 1H), 6.90 (s, 2H), 6.83 (d, 1H), 6.71 (d, 1H), 4.11 (s, 1H), 2.75-2.88 (m, 13H), 2.63 (s, 3H), 1.69-2.01 (m, 2H). 21-11²

(R)-7-amino-N-(7-fluoro-6- (piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-3- methylthieno[2,3-b]pyrazine-6- carboxamide 441 (DMSO-d₆, 400 MHz) δ (ppm): 8.63 (s, 1H), 7.82 (d, J = 7.7 Hz, 1H), 6.91 (s, 2H), 6.82 (d, J = 8.2 Hz, 2H), 4.11 (s, 1H), 2.88 (s, 10H), 2.66-2.83 (m, 1H), 2.63 (s, 5H), 2.01 (s, 1H), 1.70- 1.72 (m, 1H). 21-12²

(S)-7-amino-N-(7-fluoro-6- (piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-3- methylthieno[2,3-b]pyrazine-6- carboxamide 441 (DMSO-d₆, 400 MHz) δ (ppm): 8.64 (s, 1H), 7.82 (d, J = 7.7 Hz, 1H), 6.77-6.91 (m, 4H), 4.10 (br s, 1H), 2.64-2.95 (m, 16H), 2.63 (s, 5H), 2.01 (br s, 1H), 1.65-1.81 (m, 1H). ¹Notes on procedures: The mixture of regioisomers and enantiomers were partially separated by chiral HPLC using the chiral column Chiralpak-AD-H-SL002 and mobile phase 50% EtOH/hexanes to provide the precursor to Example 21-7 as the first eluted sample, the precursor to Example 21-8 as the second eluted sample, and a mixture of two peaks as the third eluted sample. The mixture was further separated by chiral HPLC using the chiral column Chiralpak-IC and mobile phase 30% IPA/MTBE to provide the precursor to Example 21-5 as the first eluted sample and the precursor to Example 21-6 as the second eluted sample. Stereochemistry of the separated enantiomers were arbitrarily assigned. ²Notes on procedures: The mixture of regioisomers and enantiomers were partially separated by chiral HPLC using the chiral column Chiralpak-IA and mobile phase EtOH to provide the precursor to Example 21-9 as the first eluted sample, a mixture of two peaks as the second eluted sample, and the precursor to Example 21-12 as the third eluted sample. The mixture was further separated by chiral HPLC using the chiral column (R,R)-Whelk-O1-Kromasil and mobile phase 10% EtOH/MTBE to provide the precursor to Example 21-10 as the first eluted sample and the precursor to Example 21-11 as the second eluted sample. Stereochemistry of the separated enantiomers were arbitrarily assigned.

Example 22-1. (S)-3-Amino-N-(5,8-difluoro-6-(piperazin-1-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide and Example 22-2. (R)-3-amino-N-(5,8-difluoro-6-(piperazin-1-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide

Step 1. Tert-Butyl 4-(6-(benzyloxycarbonylamino)-1,4-difluoro-5,6,7,8-tetrahydronaphthalen-2-yl)piperazine-1-carboxylate

To a solution of tert-butyl 4-(6-(benzyloxycarbonylamino)-4-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl)piperazine-1-carboxylate (3.00 g, 6.20 mmol) in 1:1 DCM/MeOH (100 mL) was added Selectfluor (2.20 g, 6.20 mmol) at 0° C. The resulting solution was stirred overnight at 20° C. Two additional portions of Selectfluor (1.1 g, 3.1 mmol) were added at 0° C. and stirred for 4 h at 20° C. The reaction mixture was then poured into 80 mL of water. The resulting mixture was extracted with 3×100 mL of DCM. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 3:1 pet. ether/ethyl acetate) to afford tert-butyl 4-(6-(benzyloxycarbonylamino)-1,4-difluoro-5,6,7,8-tetrahydronaphthalen-2-yl)piperazine-1-carboxylate as a light yellow solid. MS: (ESI, m/z): 502 [M+H]⁺.

Step 2. Tert-Butyl 4-(6-amino-1,4-difluoro-5,6,7,8-tetrahydronaphthalen-2-yl)piperazine-1-carboxylate

A solution of tert-butyl 4-(6-(benzyloxycarbonylamino)-1,4-difluoro-5,6,7,8-tetrahydronaphthalen-2-yl)piperazine-1-carboxylate (530 mg, 1.06 mmol) and palladium on carbon (100 mg, 10%) in ethyl acetate (10 mL) was stirred for 2 h at 20° C. under a hydrogen atmosphere. The solids were filtered out. The filtrate was concentrated under vacuum to afford tert-butyl 4-(6-amino-1,4-difluoro-5,6,7,8-tetrahydronaphthalen-2-yl)piperazine-1-carboxylate as a yellow solid. MS: (ESI, m/z): 368 [M+H]⁺.

Step 3. Tert-Butyl 4-(6-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-1,4-difluoro-5,6,7,8-tetrahydronaphthalen-2-yl)piperazine-1-carboxylate

A solution of tert-butyl 4-(6-amino-1,4-difluoro-5,6,7,8-tetrahydronaphthalen-2-yl)piperazine-1-carboxylate (360 mg, 0.74 mmol, 75% purity), 3-amino-6-methylthieno[2,3-b]pyridine-2-carboxylic acid (188 mg, 0.90 mmol), HBTU (343 mg, 0.90 mmol), and Et₃N (0.31 mL, 2.26 mmol) in DMA (5 mL) was stirred for 30 min at 20° C. The crude product was purified by reverse phase chromatpgraphy (Column: C₁₈ silica gel; Mobile phase A: water (0.05% formic acid), B: ACN (0% ACN up to 80% in 30 min)). The collected fraction was concentrated under vacuum to afford tert-butyl 4-(6-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-1,4-difluoro-5,6,7,8-tetrahydronaphthalen-2-yl)piperazine-1-carboxylate as a yellow solid. MS: (ESI, m/z): 558 [M+H]⁺.

Step 4. Chiral Separation

The racemate tert-butyl 4-(6-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-1,4-difluoro-5,6,7,8-tetrahydronaphthalen-2-yl)piperazine-1-carboxylate (250 mg) was separated by chiral HPLC (Column: ChiralArt Cellulose-SB, 2×25 cm, 5 μm; Mobile Phase: 30% EtOH/hexanes for 13 min). The first eluting isomer (RT=9.05 min) was concentrated under vacuum to afford (S)-tert-butyl 4-(6-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-1,4-difluoro-5,6,7,8-tetrahydronaphthalen-2-yl)piperazine-1-carboxylate as a yellow solid (stereochemistry arbitrarily assigned). The second eluting isomer (RT=10.15 min) was concentrated under vacuum to afford (R)-tert-butyl 4-(6-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-1,4-difluoro-5,6,7,8-tetrahydr-onaphthalen-2-yl)piperazine-1-carboxylate as a yellow solid (stereochemistry arbitrarily assigned). MS for both isomers: (ESI, m/z): 558 [M+H]⁺.

Step 5. (S)-3-Amino-N-(5,8-difluoro-6-(piperazin-1-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide

A solution of (S)-tert-butyl 4-(6-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-1,4-difluoro-5,6,7,8-tetrahydronaphthalen-2-yl)piperazine-1-carboxylate (60 mg, 0.11 mmol) and trifluoroacetic acid (1 mL) in DCM (3 mL) was stirred for 1 h at 20° C. The resulting mixture was concentrated under vacuum. The residue was purified by prep-HPLC (Column:)(Bridge Prep OBD C18, 30×150 mm, 5 μm; Mobile phase A: water (0.05% NH₄OH), B: ACN (15% ACN up to 50% in 7 min)). The collected fraction was lyophilized to afford (S)-3-amino-N-(5,8-difluoro-6-(piperazin-1-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide as an off-white solid. ¹H NMR (CD₃OD, 300 MHz) δ (ppm): 8.17 (d, J=8.1 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 6.67-6.65 (m, 1H), 4.25-4.17 (m, 1H), 3.14-2.97 (m, 10H), 2.82-2.70 (m, 1H), 2.64-2.54 (m, 4H), 1.89-1.74 (m, 1H). MS: (ESI, m/z): 458 [M+H]⁺.

Step 6. (R)-3-amino-N-(5,8-difluoro-6-(piperazin-1-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide

A solution of (R)-tert-butyl 4-(6-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-1,4-difluoro-5,6,7,8-tetrahydronaphthalen-2-yl)piperazine-1-carboxylate (90 mg, 0.16 mmol) and trifluoroacetic acid (1.5 mL) in DCM (4 mL) was stirred for 1 h at 20° C. The resulting mixture was concentrated under vacuum. The residue was purified by prep-HPLC (Column,)(Bridge Prep OBD C18, 30×150 mm, 5 μm; mobile phase A: water (0.05% NH₄OH), B: ACN (15% ACN up to 50% in 7 min)). The collected fraction was lyophilized to afford (R)-3-amino-N-(5,8-difluoro-6-(piperazin-1-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide as an off-white solid. ¹H NMR (DMSO-d₆, 300 MHz) δ (ppm): 8.31 (d, J=8.4 Hz, 1H), 7.64 (d, J=7.5 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.17 (s, 2H), 6.70-6.68 (m, 1H), 4.13-4.04 (m, 1H), 2.92-2.81 (m, 10H), 2.73-2.55 (m, 5H), 2.06-1.97 (m, 1H), 1.78-1.68 (m, 1H). MS: (ESI, m/z): 458 [M+H]⁺.

The following examples in Table 20 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Examples 22-1 and 22-2.

TABLE 20 LRMS Example m/z Number Structure and Compound Name [M + H]⁺ ¹H NMR 22-3¹

N-((2S)-6-(9-oxa-3,7- diazabicyclo[3.3.1]nonan-3-yl)-5,8- difluoro-1,2,3,4- tetrahydronaphthalen-2-yl)-3-amino- 6-methylthieno[2,3-b]pyridine-2- carboxamide 500 (DMSO-d₆, 300 MHz) δ (ppm): 8.31 (d, J = 8.4 Hz, 1H), 7.66 (br s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.18 (br s, 2H), 6.78-6.75 (m, 1H), 4.20-4.00 (m, 1H), 3.75-3.65 (m, 2H), 3.48-3.38 (m, 2H), 3.27-3.08 (m, 4H), 3.01-2.82 (m, 4H), 2.80-2.60 (m, 2H), 2.58 (s, 3H), 2.10-1.97 (m, 1H), 1.88-1.62 (m, 1H). 22-4¹

N-((2R)-6-(9-oxa-3,7- diazabicyclo[3.3.1]nonan-3-yl)-5,8- difluoro-1,2,3,4- tetrahydronaphthalen-2-yl)-3-amino- 6-methylthieno[2,3-b]pyridine-2- carboxamide 500 (DMSO-d₆, 300 MHz) δ (ppm): 8.31 (d, J = 8.1 Hz, 1H), 7.66 (br s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.18 (br s, 2H), 6.78-6.75 (m, 1H), 4.20-4.00 (m, 1H), 3.75-3.65 (m, 2H), 3.48-3.38 (m, 2H), 3.27-3.08 (m, 4H), 3.01-2.82 (m, 4H), 2.80-2.60 (m, 2H), 2.58 (s, 3H), 2.10-1.98 (m, 1H), 1.88-1.62 (m, 1H). 22-5²

3-amino-N-[(2S)-6-{3,8- diazabicyclo[3.2.1]octan-3-yl}-5,8- difluoro-1,2,3,4- tetrahydronaphthalen-2-yl]-6- methylthieno[2,3-b]pyridine-2- carboxamide 484 (DMSO-d₆, 300 MHz) δ (ppm): 8.30 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.17 (br s, 2H), 6.61-6.57 (m, 1H), 4.09-4.07 (m, 1H), 3.40-3.98 (m, 2H), 3.08-3.03 (m, 2H), 2.95-2.62 (m, 5H), 2.59-2.57 (m, 4H), 2.37-2.30 (m, 1H), 2.02-1.99 (m, 1H), 1.80-1.61 (m, 5H). 22-6²

3-amino-N-[(2R)-6-{3,8- diazabicyclo[3.2.1]octan-3-yl}-5,8- difluoro-1,2,3,4- tetrahydronaphthalen-2-yl]-6- methylthieno[2,3-b]pyridine-2- carboxamide 484 (DMSO-d₆, 300 MHz) δ (ppm): 8.31 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.17 (br s, 2H), 6.61-6.57 (m, 1H), 4.14-4.05 (m, 1H), 3.40-3.98 (m, 2H), 3.09-3.02 (m, 2H), 2.96-2.87 (m, 2H), 2.81-2.75 (m, 2H), 2.70-2.61 (m, 1H), 2.59-2.57 (m, 4H), 2.34-2.32 (m, 1H), 2.04-1.97 (m, 1H), 1.81-1.77 (m, 2H), 1.76-1.68 (m, 1H), 1.67-1.61 (m, 2H). ¹Notes on procedures: In Step 4, the stereoisomers were separated by chiral HPLC using the chiral column Chiralpak IG and mobile phase 15% EtOH/MTBE. Stereochemistry of the separated enantiomers were arbitrarily assigned. ²Notes on procedures: In Step 4, the stereoisomers were separated by chiral HPLC using the chiral column Chiral Art Cellulose-SB and mobile phase 10% EtOH/MTBE. Stereochemistry of the separated enantiomers were arbitrarily assigned.

Example 23-1. 7-Amino-N-[(6S)-2-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-3-methylthieno[2,3-b]pyrazine-6-carboxamide

Step 1. Benzyl N-[(6S)-2-[(3S,4S)-3-[[(tert-butoxy)carbonyl]amino]-4-methoxypyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]carbamate

A mixture of benzyl N-[(6S)-2-(trifluoromethanesulfonyloxy)-5,6,7,8-tetrahydroquinolin-6-yl]carbamate (Intermediate 47-2) (500 mg, 1.16 mmol), tert-butyl N-[(3S,4S)-4-methoxypyrrolidin-3-yl]carbamate (300 mg, 1.39 mmol), RuPhos Pd G3 (195 mg, 0.230 mmol), RuPhos (108 mg, 0.230 mmol), and Cs₂CO₃ (1.14 g, 3.49 mmol) in toluene (10 mL) was stirred for 3 h at 95° C. After cooling to 20° C., the solids were filtered out and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 5:2 pet. ether/ethyl acetate) to give benzyl N-[(6S)-2-[(3S,4S)-3-[[(tert-butoxy)carbonyl]amino]-4-methoxypyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]carbamate as a brown solid. MS (ESI, m/z): 497 [M+H]⁺.

Step 2. Tert-butyl N-[(3S,4S)-1-[(6S)-6-Amino-5,6,7,8-tetrahydroquinolin-2-yl]-4-methoxypyrrolidin-3-yl]carbamate

A mixture of benzyl N-[(6S)-2-[(3S,4S)-3-[[(tert-butoxy)carbonyl]amino]-4-methoxypyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]carbamate (450 mg, 0.910 mmol) and Palladium on carbon (450 mg, 10%) in ethyl acetate (10 mL) was stirred for 3 h at 20° C. under a hydrogen atmosphere (balloon). The solids were filtered out. The filtrate was concentrated under vacuum to give tert-butyl N-[(3S,4S)-1-[(6S)-6-amino-5,6,7,8-tetrahydroquinolin-2-yl]-4-methoxypyrrolidin-3-yl]carbamate as a white solid. MS (ESI, m/z): 362 [M+H]⁺.

Step 3. Tert-butyl N-[(3S,4S)-1-(6-[7-Amino-3-methylthieno[2,3-b]pyrazine-6-amido]-5,6,7,8-tetrahydroquinolin-2-yl)-4-methoxypyrrolidin-3-yl]carbamate

Triethylamine (0.400 mL, 2.92 mmol) and HBTU (377 mg, 0.990 mmol) were added to a stirring solution of tert-butyl N-[(3S,4S)-1-(6-amino-5,6,7,8-tetrahydroquinolin-2-yl)-4-methoxypyrrolidin-3-yl]carbamate (300 mg, 0.830 mmol) and 7-amino-3-methylthieno[2,3-b]pyrazine-6-carboxylic acid (174 mg, 0.830 mmol) in DMA (5 mL). The resulting solution was stirred for 2 h at 20° C. The mixture was purified by reversed phase chromatography (Column: C₁₈ silica gel; Mobile phase, A: water (10 mM NH₄HCO₃) and B: ACN (0% to 70% B over 30 min)). The collected fraction was concentrated under vacuum to give tert-butyl N-[(3S,4S)-1-(6-[7-amino-3-methylthieno[2,3-1)]pyrazine-6-amido]-5,6,7,8-tetrahydroquinolin-2-yl)-4-methoxypyrrolidin-3-yl]carbamate as a green solid. MS (ESI, m/z): 554 [M+H]⁺.

Step 4. 7-Amino-N-[(6S)-2-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-3-methylthieno[2,3-b]pyrazine-6-carboxamide

A solution of tert-butyl N-[(3S,4S)-1-[(6S)-6-[7-amino-3-methylthieno[2,3-b]pyrazine-6-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-4-methoxypyrrolidin-3-yl]carbamate (300 mg, 0.470 mmol) and TFA (3 mL) in DCM (10 mL) was stirred for 30 min at 20° C. and then concentrated under vacuum. The residue was treated with a solution of NH₃ in MeOH (15 mL, 7M) for 1 h at 20° C. The resulting solution was concentrated under vacuum. The residue was purified by prep-HPLC (Column: XBridge Prep C18 OBD, 19×150 mm 5 μm; Mobile Phase, A: water (containing 10 mM NH₄HCO₃) and B: ACN (20% to 42% B over 7 min)) to afford 7-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-3-methylthieno[2,3-b]pyrazine-6-carboxamide as a yellow solid. MS (ESI, m/z): 454 [M+H]⁺. ¹H NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.65 (s, 1H), 7.81 (d, J=7.6 Hz, 1H), 7.20 (d, J=8.8 Hz, 1H), 6.92 (br s, 2H), 6.23 (d, J=8.4 Hz, 1H), 4.28-4.12 (m, 1H), 3.62-3.59 (m, 2H), 3.48-3.41 (m, 2H), 3.36-3.33 (m, 4H), 3.14-3.12 (m, 1H), 2.84-2.73 (m, 4H), 2.66 (s, 3H), 2.05-2.00 (m, 1H), 1.90-1.83 (m, 1H), 1.79 (br s, 2H).

Example 23-1. 7-Amino-N-[(6S)-2-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-3-methylthieno[2,3-b]pyrazine-6-carboxamide and Example 23-2. 7-Amino-N-[(6R)-2-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-3-methylthieno[2,3-b]pyrazine-6-carboxamide

7-Amino-N-[(6S)-2-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-3-methylthieno[2,3-b]pyrazine-6-carboxamide was also obtained starting from the racemate benzyl N-[2-(trifluoromethanesulfonyloxy)-5,6,7,8-tetrahydroquinolin-6-yl]carbamate (Intermediate 47-1) and following procedures similar to Method 1. The enantiomers of the racemate 7-amino-N-[2-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-3-methylthieno[2,3-b]pyrazine-6-carboxamide were separated by chiral HPLC using the chiral column Chiralpak IE and the eluent system 50% EtOH/MTBE (containing 2 mM NH₃ in MeOH) to provide 7-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-3-methylthieno[2,3-b]pyrazine-6-carboxamide as a yellow solid as the first eluted isomer and 7-amino-N-[(6R)-2-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-3-methylthieno[2,3-b]pyrazine-6-carboxamide as a yellow solid as the second eluted isomer. ¹H NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.65 (s, 1H), 7.83 (d, J=7.6 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 6.93 (br, 2H), 6.24 (d, J=8.8 Hz, 1H), 4.20-4.11 (m, 1H), 3.63-3.56 (m, 2H), 3.47-3.44 (m, 2H), 3.33 (s, 3H), 3.15-3.13 (m, 1H), 2.84-2.73 (m, 4H), 2.65 (s, 3H), 2.05-1.98 (m, 1H), 1.91-1.83 (m, 2H). MS (ESI, m/z): 454 [M+H]⁺.

The following examples in Table 21 were prepared using standard chemical manipulations and procedures similar to Method 1 (or Method 2 where indicated) for the preparation of Example 23-1.

TABLE 21 LRMS Example m/z Number Structure and Compound Name [M + H]⁺ ¹H NMR 23-3¹

3-amino-N-[(6S)-2-[(3S,4S)-3-amino- 4-methoxypyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-4,6- dimethylthieno[2,3-b]pyridine-2- carboxamide 467 (DMSO-d₆, 400 MHz) δ (ppm): 7.59 (d, J = 7.6 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.04 (s, 1H), 6.81 (br s, 2H), 6.23 (d, J = 8.4 Hz, 1H), 4.08-4.15 (m, 1H), 3.61-3.63 (m, 2H), 3.43-3.33 (m, 3H), 3.30 (s, 3H), 3.13-3.11 (m, 1H), 2.81-2.69 (m, 7H), 2.58 (s, 3H), 1.99-1.72 (m, 3H). 23-4²

3-amino-N-[(6S)-2-[(3S,4S)-3-amino- 4-methoxypyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2- carboxamide 453 (DMSO-d₆, 400 MHz) δ (ppm): 8.31 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.20-7.17 (m, 3H), 6.23 (d, J = 8.4 Hz, 1H), 4.16-4.07 (m, 1H), 3.62-3.58 (m, 2H), 3.47-3.41 (m, 2H), 3.29 (s, 3H), 3.12 (d, J = 8.4 Hz, 1H), 2.82- 2.68 (m, 4H), 2.59 (s, 3H), 2.01-1.98 (m, 1H), 1.82-1.74 (m, 2H). 23-5²

3-amino-N-[(6R)-2-[(3S,4S)-3- amino-4-methoxypyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2- carboxamide 453 (DMSO-d₆, 400 MHz) δ (ppm): 8.30 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.20-7.18 (m, 3H), 6.22 (d, J = 8.4 Hz, 1H), 4.14-4.07 (m, 1H), 3.61-3.57 (m, 2H), 3.44-3.42 (m, 2H), 3.29 (s, 3H), 3.13 (d, J = 8.0 Hz, 1H), 2.81- 2.68 (m, 4H), 2.58 (s, 3H), 2.01-1.98 (m, 1H), 1.82-1.74 (m, 2H). 23-6

7-amino-3-methyl-N-[(6S)-2- (piperazin-1-yl)-5,6,7,8- tetrahydroquinolin-6-yl]thieno[2,3- b]pyrazine-6-carboxamide 424 (DMSO-d₆, 400 MHz) δ (ppm): 8.65 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 6.92 (br s, 2H), 6.63-6.57 (m, 1H), 4.18-4.14 (m, 1H), 3.41-3.33 (m, 3H), 2.86-2.70 (m, 9H), 2.56 (s, 3H), 2.04-2.01 (m, 1H), 1.92- 1.82 (m, 1H). 23-7³

3-amino-6-methyl-N-[(6S)-2- (piperazin-1-yl)-5,6,7,8- tetrahydroquinolin-6-yl]thieno[2,3- b]pyridine-2-carboxamide 423 (DMSO-d₆, 300 MHz) δ (ppm): 8.31 (d, J = 8.0 Hz, 1H) 7.59 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.17 (br s, 2H), 6.58 (d, J = 8.4 Hz, 1H), 4.18- 4.16 (m, 1H), 3.34-3.32 (m, 4H), 2.94-2.68 (m, 8H), 2.58 (s, 3H), 2.08- 1.90 (m, 1H), 1.88-1.80 (m, 1H). 23-8³

3-amino-6-methyl-N-[(6R)-2- (piperazin-1-yl)-5,6,7,8- tetrahydroquinolin-6-yl]thieno[2,3- b]pyridine-2-carboxamide 423 (DMSO-d₆, 300 MHz) δ (ppm): 8.31 (d, J = 8.0 Hz, 1H) 7.59 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.17 (br s, 2H), 6.58 (d, J = 8.4 Hz, 1H), 4.18- 4.16 (m, 1H), 3.34-3.32 (m, 4H), 2.94-2.68 (m, 8H), 2.58 (s, 3H), 2.08- 1.90 (m, 1H), 1.88-1.80 (m, 1H). 23-9⁴

3-amino-6-methyl-N-[(6R)-2- (piperazin-1-yl)-5,6,7,8- tetrahydroquinolin-6-yl]thieno[2,3- b]pyridine-2-carboxamide 429 (DMSO-d₆, 400 MHz) δ (ppm): 7.59 (d, J = 7.6 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.08 (br s, 2H), 6.58 (d, J = 8.4 Hz, 1H), 4.13-4.07 (m, 1H), 3.41- 3.32 (m, 4H), 2.79-2.68 (m, 11H), 2.00-1.97 (m, 1H), 1.86-1.80 (m, 1H). 23-10

3-amino-N-[(6S)-2-{3,6- diazabicyclo[3.1.1]heptan-3-yl}- 5,6,7,8-tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2- carboxamide 435 (DMSO-d₆, 400 MHz) δ (ppm): 8.31 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.16 (br s, 2H), 6.40 (d, J = 8.4 Hz, 1H), 4.18- 4.12 (m, 1H), 3.67-3.66 (m, 2H), 3.57-3.50 (m, 4H), 3.40-3.33 (m, 2H), 2.83-2.75 (m, 4H), 2.59 (s, 3H), 2.03- 2.00 (m, 1H), 1.89-1.84 (m, 1H), 1.44 (d, J = 8.0 Hz, 1H). 23-11

7-amino-N-[(6S)-2-{3,6- diazabicyclo[3.1.1]heptan-3-yl}- 5,6,7,8-tetrahydroquinolin-6-yl]-3- methylthieno[2,3-b]pyrazine-6- carboxamide 436 (DMSO-d₆, 400 MHz) δ (ppm): 8.65 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 6.92 (br s, 2H), 6.40 (d, J = 9.2 Hz, 1H), 4.19-4.16 (m, 1H), 3.68-3.66 (m, 2H), 3.60-3.51 (m, 4H), 3.33-3.20 (m, 2H), 2.83-2.76 (m, 4H), 2.66 (s, 3H), 2.05-2.02 (m, 1H), 1.90-1.87 (m, 1H), 1.44 (d, J = 8.8 Hz, 1H). 23-12

3-amino-N-[(6S)-2-{3,8- diazabicyclo[3.2.1]octan-3-yl}- 5,6,7,8-tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2- carboxamide 449 (DMSO-d₆, 400 MHz) δ (ppm): 8.31 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 7.2 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.22-7.15 (m, 3H), 6.45 (d, J = 8.8 Hz, 1H), 4.14 (br s, 1H), 3.77-3.75 (m, 2H), 3.47 (s, 2H), 2.82-2.68 (m, 6H), 2.59 (s, 3H), 2.02-1.83 (m, 2H), 1.63-1.54 (m, 4H). 23-13

7-amino-N-{(6S)-2-{3,8- diazabicyclo[3.2.1]octan-3-yl}- 5,6,7,8-tetrahydroquinolin-6-yl]-3- methylthieno[2,3-b]pyrazine-6- carboxamide 450 (DMSO-d₆, 300 MHz) δ (ppm): 8.65 (s, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 6.93 (br s, 2H), 6.47-6.42 (m, 1H), 4.16 (br s, 1H), 3.77-3.73 (m, 2H), 2.85-2.66 (m, 6H), 2.58 (s, 3H), 2.41 (s, 1H), 2.03-1.81 (m, 2H), 1.67-1.54 (m, 4H). 23-14¹

3-amino-4,6-dimethyl-N-[(6S)-2- (piperazin-1-yl)-5,6,7,8- tetrahydroquinolin-6-yl]thieno[2,3- b]pyridine-2-carboxamide 437 (DMSO-d₆, 400 MHz) δ (ppm): 7.61 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 7.14 (s, 1H), 6.82 (br, 2H), 6.58 (d, J = 8.8 Hz, 1H), 4.16-4.14 (m, 1H), 3.41-3.33 (m, 6H), 2.82-2.73 (m, 12H), 2.00-1.99 (m,1H), 1.88- 1.83 (m, 1H). 23-15⁵

3-amino-6-methyl-N-[(6S)-2-[(3S)-3- methylpiperazin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]thieno[2,3- b]pyridine-2-carboxamide 437 (DMSO-d₆, 400 MHz) δ (ppm): 8.31 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 8.8 Hz, 1H), 7.16 (br s, 2H), 6.59 (d, J = 8.4 Hz, 1H), 4.14- 4.00 (m, 3H), 2.94-2.91 (m, 1H), 2.84-2.65 (m, 6H), 2.63-2.60 (m, 4H), 2.26-2.20 (m, 1H), 1.99-2.03 (m, 2H), 1.91-1.83 (m, 1H), 1.03-1.01 (d, J = 8.0 Hz, 1H). 23-16⁶

3-amino-6-methyl-N-[(6S)-2-[(3R)-3- methylpiperazin-l-yl]-5,6,7,8- tetrahydroquinolin-6-yl]thieno[2,3- b]pyridine-2-carboxamide 437 (DMSO-d₆, 400 MHz) δ (ppm): 8.31 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.16 (br s, 2H), 6.59 (d, J = 8.0 Hz, 1H), 4.13- 4.00 (m, 3H), 2.94-2.61 (m, 7H), 2.59 (s, 3H), 2.26-2.20 (m, 2H), 1.99-1.83 (m, 2H), 1.02 (d, J = 6.4 Hz, 3H). 23-17⁷

3-amino-N-[(6S)-4-fluoro-2- (piperazin-1-yl)-5,6,7,8- tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2- carboxamide 441 (DMSO-d₆, 400 MHz) δ (ppm): 8.31 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 7.2 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.17 (br s, 2H), 6.48 (d, J = 12.8 Hz, 1H), 4.22-4.12 (m, 1H), 3.36-3.20 (m, 4H), 2.90-2.84 (m, 1H), 2.82-2.75 (m, 6H), 2.59-2.54 (m, 4H), 2.04-1.98 (m, 1H), 1.92-1.83 (m, 1H). 23-18⁸

N-((6S)-2-(3,8- diazabicyclo[3.2.1]octan-3-yl)-4- fluoro-5,6,7,8-tetrahydroquinolin-6- yl)-3-amino-6-methylthieno[2,3- b]pyridine-2-carboxamide 467 (DMSO-d₆, 400 MHz) δ (ppm): 8.31 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.17 (br s, 2H), 6.33 (d, J = 12.6 Hz, 1H), 4.16-4.14 (m, 1H), 3.76-3.73 (m, 2H), 3.48-3.46 (m, 2H), 2.89-2.74 (m, 5H), 2.59-2.53 (m, 4H), 1.98-1.83 (m, 2H), 1.75-1.63 (m, 4 H). ¹Notes on procedures: In Step 3, the carboxylic acid Intermediate 21 was used. ²Notes on procedures: Following Method 2, the stereoisomers were separated by chiral HPLC using the chiral column Chiralpak IE and the eluent gradient 30% to 35% EtOH/MTBE (containing 2 mM NH₃ in MeOH). ³Notes on procedures: Following Method 2, the stereoisomers were separated by chiral HPLC using the chiral column Chiralpak ID-3 and mobile phase 30% EtOH/(hexanes:DCM = 3:1, containing 0.1% DIEA). ⁴Notes on procedures: In Step 3, the carboxylic acid Intermediate 24 was used. ⁵Notes on procedures: In Step 1, tert-butyl (2S)-2-methylpiperazine-1-carboxylate was used. ⁶Notes on procedures: In Step 1, tert-butyl (2R)-2-methylpiperazine-1-carboxylate was used. ⁷Notes on procedures: Skipping Step 1 and Step 2, the amine Intermediate 52-1 was used in Step 3. ⁸Notes on procedures: Skipping Step 1 and Step 2, the amine Intermediate 52-2 was used in Step 3.

Example 24-1. 3-Amino-N-[(6S)-2-[(3R,4R)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide

Step 1. Benzyl N-[(6S)-2-[(3R,4R)-3-[[(tert-butoxy)carbonyl]amino]-4-(methoxymethyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]carbamate

A mixture of benzyl N-[(6S)-2-(trifluoromethanesulfonyloxy)-5,6,7,8-tetrahydroquinolin-6-yl]carbamate (Intermediate 47-2) (800 mg, 1.85 mmol), tert-butyl N-[(3R,4R)-4-(methoxymethyl)pyrrolidin-3-yl]carbamate (Intermediate 48-2) (513 mg, 2.23 mmol), RuPhos Pd G3 (155 mg, 0.186 mmol), RuPhos (86.7 mg, 0.186 mmol) and Cs₂CO₃ (1.21 g, 3.71 mmol) in toluene (10 mL) was stirred for 3 h at 90° C. After cooling to 25° C., the solids were filtered out. The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:2 ethyl acetate/pet. ether) to afford benzyl N-[(6S)-2-[(3R,4R)-3-[[tert-butoxy)carbonyl]amino]-4-(methoxymethyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]carbamate as a white solid. MS (ESI, m/z): 511 [M+H]⁺.

Step 2. Tert-Butyl N-[1-[(6S)-6-amino-5,6,7,8-tetrahydroquinolin-2-yl]-4-(methoxymethyl)pyrrolidin-3-yl]carbamate

A mixture of benzyl N-[(6S)-2-[(3R,4R)-3-[[(tert-butoxy)carbonyl]amino]-4-(methoxymethyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]carbamate (550 mg, 1.07 mmol) and palladium on carbon (80 mg, 10%) in ethyl acetate (5 mL) was stirred for 1 h at 25° C. under a hydrogen atmosphere (balloon). The solids were filtered out. The filtrate was concentrated under vacuum to give tert-butyl N-[1-[(6S)-6-amino-5,6,7,8-tetrahydroquinolin-2-yl]-4-(methoxymethyl)pyrrolidin-3-yl]carbamate as a white solid (crude). MS (ESI, m/z): 377 [M+H]⁺.

Step 3. Tert-Butyl N-[(3R,4R)-1-[(6S)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-4-(methoxymethyl)pyrrolidin-3-yl]carbamate

Et₃N (0.50 mL, 3.58 mmol) and HBTU (453 mg, 1.19 mmol) were added to a stirring solution of tert-butyl N-[(3R,4R)-1-[(6S)-6-amino-5,6,7,8-tetrahydroquinolin-2-yl]-4-(methoxymethyl)pyrrolidin-3-yl]carbamate (450 mg, 1.19 mmol) and 3-amino-6-methylthieno[2,3-b]pyridine-2-carboxylic acid (248 mg, 1.19 mmol) in DMA (4 mL). The resulting solution was stirred for 2 h at 25° C. The mixture was purified by reverse phase chromatography (Column: C₁₈ silica gel; Mobile phase, A: water (containing 0.05% TFA) and B: ACN (15% to 90% over 25 min)). The collected fraction was concentrated under vacuum to give tert-butyl N-[(3R,4R)-1-[(6S)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-4-(methoxymethyl)pyrrolidin-3-yl]carbamate as a yellow solid. MS (ESI, m/z): 567 [M+H]⁺.

Step 4. 3-Amino-N-[(6S)-2-[(3R,4R)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide

A solution of tert-butyl N-[(3R,4R)-1-[(65)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-4-(methoxymethyl)pyrrolidin-3-yl]carbamate (450 mg, 0.794 mmol) and TFA (3 mL) in DCM (12 mL) was stirred for 1 h at 25° C. The mixture was concentrated under vacuum. The residue was treated with a solution of NH₃ in MeOH (2 mL, 7M). The resulting mixture was stirred for 10 min and concentrated under vacuum. The residue was purified by prep-HPLC (Column: XBridge Shield RP18 OBD, 30×150 mm, 5 μm; Mobile Phase A: water (10 mM NH₄HCO₃) and B: ACN (27% to 37% over 7 min); Flow rate: 60 mL/min). The collected fraction was lyophilized to give 3-amino-N-[(6S)-2-[(3R,4R)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide as a white solid. MS (ESI, m/z): 467 [M+H]⁺. ¹H NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.31 (d, J=8.0 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.19-7.17 (m, 3H), 6.20 (d, J=8.4 Hz, 1H), 4.15-4.08 (m, 1H), 3.61-3.51 (m, 2H), 3.52-3.35 (m, 3H), 3.29 (s, 3H), 3.25-3.15 (m, 2H), 2.81-2.64 (m, 4H), 2.60 (s, 3H), 2.49-2.38 (m, 1H), 2.09-1.98 (m, 1H), 1.91-1.80 (m, 1H), 1.61 (br s, 2H).

Example 24-1. 3-Amino-N-[(6S)-2-[(3R,4R)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide and Example 24-2. 3-Amino-N-[(6S)-2-[(3S,4S)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide

3-Amino-N-[(6S)-2-[(3R,4R)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide was also obtained starting from the cis racemate tert-butyl N-[4-(methoxymethyl)pyrrolidin-3-yl]carbamate (Intermediate 48-1) and following procedures similar to Method 1. The enantiomers of the cis racemate tert-butyl N-[1-[(6S)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-4-(methoxymethyl)pyrrolidin-3-yl]carbamate (Step 3 product) were separated by chiral HPLC using the chiral column Chiralpak IA and Mobile Phase, 50% A: hexanes:DCM=3:1 and 50% B: EtOH (containing 0.1% Et₂NH) to provide tert-butyl N-[(3R,4R)-1-[(6S)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-4-(methoxymethyl)pyrrolidin-3-yl]carbamate as a white solid as the first eluted isomer (RT=9.3 min) and tert-butyl N-[(3S,4S)-1-[(6S)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-4-(methoxymethyl)pyrrolidin-3-yl]carbamate as a white solid as the second eluted isomer (RT=11.3 min).

3-Amino-N-[(6S)-2-[(3S,4S)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide was obtained from conversion of tert-butyl N-[(3S,4S)-1-[(6S)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-4-(methoxymethyl)pyrrolidin-3-yl]carbamate following procedures similar to Method 1, Step 4. ¹H NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.30 (d, J=8.0 Hz, 1H), 7.56 (br s, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.18-7.16 (m, 3H), 6.20 (d, J=8.4 Hz, 1H), 4.18-4.09 (m, 1H), 3.61-3.51 (m, 2H), 3.50-3.39 (m, 3H), 3.28 (s, 3H), 3.21-3.17 (m, 2H), 2.81-2.64 (m, 4H), 2.67 (s, 3H), 2.46-2.40 (m, 1H), 2.09-1.91 (m, 1H), 1.91-1.80 (m, 1H), 1.55 (br s, 2H). MS (ESI, m/z): 467 [M+H]⁺.

Example 25. 3-Amino-N-[(6S)-2-[(3S,4R)-3-amino-4-(difluoromethyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide

Step 1. Benzyl N-[(6S)-2-[(3S,4R)-3-[[(tert-butoxy)carbonyl]amino]-4-(difluoromethyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]carbamate

A mixture of benzyl N-[(6S)-2-(trifluoromethanesulfonyloxy)-5,6,7,8-tetrahydroquinolin-6-yl]carbamate (Intermediate 47-2) (480 mg, 1.09 mmol), tert-butyl N-[(3S,4R)-4-(difluoromethyl)pyrrolidin-3-yl]carbamate (Intermediate 51-2) (284 mg, 1.20 mmol), RuPhos (51.0 mg, 0.109 mmol), RuPhos Pd G3 (91.0 mg, 0.109 mmol) and Cs₂CO₃ (890 mg, 2.73 mmol) in toluene (10 mL) was stirred for 4 h at 95° C. After cooled to 25° C., the solids were filtered out. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 1:1 ethyl acetate/pet. ether) to afford benzyl N-[(6S)-2-[(3S,4R)-3-[[(tert-butoxy)carbonyl]amino]-4-(difluoromethyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]carbamate as a white solid. MS (ESI, m/z): 517 [M+H]⁺.

Step 2. Tert-butyl N-[(3S,4R)-1-[(6S)-6-amino-5,6,7,8-tetrahydroquinolin-2-yl]-4-(difluoromethyl)pyrrolidin-3-yl]carbamate

A mixture of benzyl N-[(6S)-2-[(3S,4R)-3-[[(tert-butoxy)carbonyl]amino]-4-(difluoromethyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]carbamate (350 mg, 0.664 mmol) and Pd/C (350 mg, 10%) in ethyl acetate (10 mL) was stirred 2 h at 25° C. under hydrogen atmosphere. The solids were filtered out and the filter cake was washed with ethyl acetate (3×10 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl N-[(3S,4R)-1-[(6S)-6-amino-5,6,7,8-tetrahydroquinolin-2-yl]-4-(difluoromethyl)pyrrolidin-3-yl]carbamate as a brown solid. MS (ESI, m/z): 383 [M+H]⁺.

Step 3. Tert-Butyl N-[(3S,4R)-1-[(6S)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-4-(difluoromethyl)pyrrolidin-3-yl]carbamate

A solution of tert-butyl N-[(3S,4R)-1-[(6S)-6-amino-5,6,7,8-tetrahydroquinolin-2-yl]-4-(difluoromethyl)pyrrolidin-3-yl]carbamate (240 mg, 0.615 mmol), 3-amino-6-methylthieno[2,3-b]pyridine-2-carboxylic acid (141 mg, 0.677 mmol), Et₃N (0.260 mL, 1.85 mmol) and HBTU (280 mg, 0.738 mmol) in DMA (5 mL) was stirred for 6 h at 25° C. The mixture was purified by reverse phase chromatography (Column: C₁₈ silica gel; Mobile phase, A: water (containing 0.1% TFA) and B: ACN (0% to 60% in 30 min)) to afford tert-butyl N-[(3S,4R)-1-[(6S)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-4-(difluoromethyl)pyrrolidin-3-yl]carbamate as a yellow solid. MS (ESI, m/z): 573 [M+H]⁺.

Step 4. 3-Amino-N-[(6S)-2-[(3S,4R)-3-amino-4-(difluoromethyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide

To a stirring solution of tert-butyl N-[(3S,4R)-1-[(6S)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-4-(difluoromethyl)pyrrolidin-3-yl]carbamate (300 mg, 0.513 mmol) in DCM (15 mL) was added TFA (5 mL) dropwise at 0° C. The resulting mixture was stirred for 40 min at 25° C. The resulting mixture was concentrated under vacuum. The resulting mixture was concentrated under vacuum. The residue was treated with NH₃ (15 mL, 7 M in MeOH). The solution was stirred for 30 min at 25° C. and concentrated under vacuum. The residue was purified by prep-HPLC (Column: XBridge Prep Phenyl OBD, 19×150 mm, 5 μm; Mobile Phase, A: water (10 mM NR₄HCO₃) and B: ACN (20% to 37% in 8 min); Flow rate: 60 mL/min). The product fraction was lyophilized to afford 3-amino-N-[(6S)-2-[(3S,4R)-3-amino-4-(difluoromethyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide as a white solid. MS (ESI, m/z): 473 [M+H]⁺. ¹H NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.31 (d, J=8.0 Hz, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.17 (br s, 2H), 6.34-6.05 (m, 2H), 3.68-3.57 (m, 2H), 3.51-3.48 (m, 1H), 3.39-3.77 (m, 1H), 3.04-3.00 (m, 1H), 2.81-2.75 (m, 4H), 2.72 (s, 3H), 2.48-2.42 (m, 1H), 2.08-1.91 (m, 1H), 1.90-1.78 (m, 3H).

Example 26-1. 3-Amino-N-[(6S)-2-[(3S,4R)-3-(methoxymethyl)-4-(methylamino)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide and Example 26-2. 3-Amino-N-[(6S)-2-[(3R,4S)-3-(methoxymethyl)-4-(methylamino)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide

Step 1. trans-Benzyl N-[(6S)-2-(3-[[(tert-butoxy)carbonyl](methyl)amino]-4-(methoxymethyl)pyrrolidin-1-yl)-5,6,7,8-tetrahydroquinolin-6-yl]carbamate

A mixture of benzyl N-[(6S)-2-(trifluoromethanesulfonyloxy)-5,6,7,8-tetrahydroquinolin-6-yl]carbamate (Intermediate 47-2) (200 mg, 0.446 mmol), trans-tert-butyl N-[4-(methoxymethyl)pyrrolidin-3-yl]-N-methylcarbamate (Intermediate 53) (121 mg, 0.446 mmol), RuPhos (42.0 mg, 0.090 mmol), RuPhos Pd G3 (38.0 mg, 0.045 mmol) and Cs₂CO₃ (291 mg, 0.893 mmol) in toluene (4 mL) was stirred for 3 h at 90° C. The solids were filtered out. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 1:1 ethyl acetate/pet. ether) to afford trans-benzyl N-[(6S)-2-(3-[[(tert-butoxy)carbonyl](methyl)amino]-4-(methoxymethyl)pyrrolidin-1-yl)-5,6,7,8-tetrahydroquinolin-6-yl]carbamate as a yellow solid. MS (ESI, m/z): 525 [M+H]⁺.

Step 2. trans-tert-Butyl N-[1-[(6S)-6-amino-5,6,7,8-tetrahydroquinolin-2-yl]-4-(methoxymethyl)pyrrolidin-3-yl]-N-methylcarbamate

A mixture of trans-benzyl N-[(6S)-2-(3-[[(tert-butoxy)carbonyl](methyl)amino]-4-(methoxymethyl)pyrrolidin-1-yl)-5,6,7,8-tetrahydroquinolin-6-yl]carbamate (180 mg, 0.326 mmol) and palladium on carbon (180 mg, 10%) in ethyl acetate (10 mL) was stirred for 3 h at 25° C. under hydrogen atmosphere (balloon). The solids were filtered out. The filtrate was concentrated under reduced pressure to afford trans-tert-butyl N-[1-[(6S)-6-amino-5,6,7,8-tetrahydroquinolin-2-yl]-4-(methoxymethyl)pyrrolidin-3-yl]-N-methylcarbamate as a white solid. MS (ESI, m/z): 391 [M+H]⁺.

Step 3. trans-tert-Butyl N-[1-[(6S)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-4-(methoxymethyl)pyrrolidin-3-yl]-N-methylcarbamate

HBTU (122 mg, 0.322 mmol) was added to a stirring solution of trans-tert-butyl N-[1-[(6S)-6-amino-5,6,7,8-tetrahydroquinolin-2-yl]-4-(methoxymethyl)pyrrolidin-3-yl]-N-methylcarbamate (70.0 mg, 0.179 mmol), 3-amino-6-methylthieno[2,3-b]pyridine-2-carboxylic acid (39.0 mg, 0.189 mmol) and Et₃N (0.075 mL, 0.537 mmol) in DMA (2 mL). The resulting solution was stirred for 1 h at 25° C. The resulting mixture was purified by reverse phase chromatography (Column: C₁₈ silica gel; Mobile phase, A: water (containing 10 mmol/L NH₄HCO₃) and B: ACN (5% to 80% in 30 min)). The collected fraction was concentrated under vacuum to give trans-tert-butyl N-[1-[(6S)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-4-(methoxymethyl)pyrrolidin-3-yl]-N-methylcarbamate as a yellow solid. MS (ESI, m/z): 581 [M+H]⁺.

Step 4. Tert-Butyl N-[(3R,4S)-1-[(6S)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-4-(methoxymethyl)pyrrolidin-3-yl]-N-methylcarbamate and Tert-butyl N-[(3S,4R)-1-[(6S)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-4-(methoxymethyl)pyrrolidin-3-yl]-N-methylcarbamate

trans-tert-Butyl N-[1-[(6S)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-4-(methoxymethyl)pyrrolidin-3-yl]-N-methylcarbamate (40.0 mg, 0.0690 mmol) was separated by chiral HPLC (Column: Chiralpak IA, 2×25 cm, 5 μm; Mobile phase, A: hexanes:DCM=3:1 (containing 0.1% Et₂NH) and B: EtOH (hold 30% in 30 min); Flow rate: 12 mL/min). The first eluting isomer (RT=11.8 min) was collected and concentrated under vacuum to give a yellow solid, stereochemistry on the pyrrolidine arbitrarily assigned as tert-butyl N-[(3S,4R)-1-[(6S)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-4-(methoxymethyl)pyrrolidin-3-yl]-N-methylcarbamate. The second eluting isomer (RT=21.4 min) was collected and concentrated under vacuum to give a yellow solid, stereochemistry on the pyrrolidine arbitrarily assigned as tert-butyl N-[(3R,4S)-1-[(6S)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-4-(methoxymethyl)pyrrolidin-3-yl]-N-methylcarbamate. MS (ESI, m/z): 581 [M+H]⁺.

Step 5. 3-Amino-N-[(6S)-2-[(3S,4R)-3-(methoxymethyl)-4-(methylamino)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide

A solution of tert-butyl N-[(3S,4R)-1-[(6S)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-4-(methoxymethyl)pyrrolidin-3-yl]-N-methylcarbamate (11.0 mg, 0.0190 mmol) and TFA (0.500 mL) in DCM (1.50 mL) was stirred for 30 min at 25° C. The resulting mixture was concentrated under vacuum. The residue was treated with a solution of NH₃ (2.00 mL, 7M in MeOH). The resulting solution was stirred for 30 min at 25° C. and concentrated under vacuum. The residue was purified by prep-HPLC (Column: XBridge Shield RP18 OBD, 5 μm, 19×150 mm; Mobile Phase A: water (10 mM NH₄HCO₃) and B: ACN (0% to 55% in 7 min); Flow rate: 25 mL/min). The collected fraction was lyophilized to give 3-amino-N-[(6S)-2-[(3S,4R)-3-(methoxymethyl)-4-(methylamino)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide as a white solid. MS (ESI, m/z): 481 [M+H]⁺. ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.31 (d, J=8.4 Hz, 1H), 7.59 (br s, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.20-7.17 (m, 3H), 6.24 (d, J=8.0 Hz, 1H), 4.14-4.10 (m, 1H), 3.64-3.59 (m, 1H), 3.54-3.50 (m, 1H), 3.46-3.27 (m, 8H), 3.17-3.10 (m, 5H), 2.55 (s, 3H), 2.35-2.30 (m, 4H), 2.02-1.97 (m, 1H), 1.88-1.82 (m, 1H).

Step 6. 3-Amino-N-[(6S)-2-[(3R,4S)-3-(methoxymethyl)-4-(methylamino)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide

A solution of tert-butyl N-[(3R,4S)-1-[(6S)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-4-(methoxymethyl)pyrrolidin-3-yl]-N-methylcarbamate (13.0 mg, 0.022 mmol) and TFA (0.500 mL) in DCM (1.50 mL) was stirred for 30 min at 25° C. The resulting mixture was concentrated under vacuum. The residue was treated with a solution of NH₃ (2.00 mL, 7M in MeOH). The resulting solution was stirred for 30 min at 25° C. and concentrated under vacuum. The residue was purified by prep-HPLC (Column: XBridge Shield RP18 OBD, 5 μm, 19×150 mm; Mobile phase, A: water (10 mM NH₄HCO₃) and B: ACN (20% to 45% in 7 min); Flow rate: 25 mL/min). The collected fraction was lyophilized to give 3-amino-N-[(65)-2-[(3R,4S)-3-(methoxymethyl)-4-(methylamino)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide as a white solid. MS (ESI, m/z): 481 [M+H]⁺. ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.31 (d, J=8.0 Hz, 1H), 7.59 (br s, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.20-7.17 (m, 3H), 6.24 (d, J=8.4 Hz, 1H), 4.14-4.10 (m, 1H), 3.65-3.60 (m, 1H), 3.55-3.51 (m, 1H), 3.46-3.27 (m, 5H), 3.16-3.10 (m, 2H), 3.02-3.00 (m, 1H), 2.76-2.72 (m, 4H), 2.59 (s, 3H), 2.34-2.32 (m, 4H), 2.02-1.97 (m, 1H), 1.88-1.82 (m, 1H).

Example 27-1. 3-Amino-N-[(6S)-2-[(3R,4R)-3-amino-4-(fluoromethyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide and Example 27-2. 3-Amino-N-[(6S)-2-[(3S,4S)-3-amino-4-(fluoromethyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide

Step 1. Cis-Benzyl N-[(6S)-2-(3-[[(tert-butoxy)carbonyl]amino]-4-(fluoromethyl)pyrrolidin-1-yl)-5,6,7,8-tetrahydroquinolin-6-yl]carbamate

A mixture of cis-tert-butyl N-[4-(fluoromethyl)pyrrolidin-3-yl]carbamate (Intermediate 54) (150 mg, 0.687 mmol), benzyl N-[(6S)-2-(trifluoromethanesulfonyloxy)-5,6,7,8-tetrahydroquinolin-6-yl]carbamate (Intermediate 47-2) (150 mg, 0.342 mmol), RuPhos (16.0 mg, 0.034 mmol), RuPhos Pd G3 (29.0 mg, 0.035 mmol) and Cs₂CO₃ (278 mg, 0.853 mmol) in toluene (5 mL) was stirred for 2 h at 95° C. After cooled to 25° C., the solids were filtered out. The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:1 ethyl acetate/pet. ether) to afford cis-benzyl N-[(6S)-2-(3-[[(tert-butoxy)carbonyl]amino]-4-(fluoromethyl)pyrrolidin-1-yl)-5,6,7,8-tetrahydroquinolin-6-yl]carbamate as a white solid. MS (ESI, m/z): 499 [M+H]⁺.

Step 2. Cis-tert-Butyl N-[1-[(6S)-6-amino-5,6,7,8-tetrahydroquinolin-2-yl]-4-(fluoromethyl)pyrrolidin-3-yl]carbamate

A mixture of cis-benzyl N-[(6S)-2-(3-[[(tert-butoxy)carbonyl]amino]-4-(fluoromethyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]carbamate (130 mg, 0.256 mmol) and Palladium on carbon (130 mg, 10%) in ethyl acetate (5 mL) was stirred for 2 h at 25° C. under hydrogen atmosphere (balloon). The resulting mixture was filtered. The filtrate was concentrated under reduced pressure to afford cis-tert-butyl N-[1-[(6S)-6-amino-5,6,7,8-tetrahydroquinolin-2-yl]-4-(fluoromethyl)pyrrolidin-3-yl]carbamate as a brown solid. MS (ESI, m/z): 365 [M+H]⁺.

Step 3. Cis-tert-Butyl N-[1-[(6S)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-4-(fluoromethyl)pyrrolidin-3-yl]carbamate

HBTU (92.0 mg, 0.243 mmol) was added to a solution of cis-tert-butyl N-[(3R,4R)-1-[(6S)-6-amino-5,6,7,8-tetrahydroquinolin-2-yl]-4-(fluoromethyl)pyrrolidin-3-yl]carbamate (75.0 mg, 0.202 mmol), 3-amino-6-methylthieno[2,3-b]pyridine-2-carboxylic acid (45.0 mg, 0.216 mmol) and Et₃N (0.084 mL, 0.603 mmol) in DMA (3 mL). The resulting solution was stirred for 1 h at 25° C. The mixture was purified by reverse phase chromatography (Column: C₁₈ silica gel; Mobile phase, A: water (containing 10 mmol/L NH₄HCO₃) and B: ACN (0% to 100% in 30 min)) to afford cis-tert-butyl N-[1-[(6S)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-4-(fluoromethyl)pyrrolidin-3-yl]carbamate as a yellow solid. MS (ESI, m/z): 555 [M+H]⁺.

Step 4. Tert-Butyl N-[(3R,4R)-1-[(6S)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-4-(fluoromethyl)pyrrolidin-3-yl]carbamate and tert-Butyl N-[(3S,4S)-1-[(6S)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-4-(fluoromethyl)pyrrolidin-3-yl]carbamate

cis-tert-Butyl N-[1-[(6S)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-4-(fluoromethyl)pyrrolidin-3-yl]carbamate (70.0 mg, 0.124 mmol) was separated by chiral HPLC (Column: Chiralpak IG, 20×250 mm, 5 μm; Mobile phase, A: hexanes:DCM=3:1 (containing 0.1% Et₂NH) and B: IPA (hold 30% in 16 min)). The first eluting isomer (RT=10.09 min) was collected and concentrated under vacuum to afford a white solid, stereochemistry on the pyrrolidine arbitrarily assigned as tert-butyl N-[(3R,4R)-1-[(6S)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-4-(fluoromethyl)pyrrolidin-3-yl]carbamate. The second eluting isomer (RT=13.22 min) was collected and concentrated under vacuum to afford a white solid, stereochemistry on the pyrrolidine arbitrarily assigned as tert-butyl N-[(3S,4S)-1-[(6S)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-4-(fluoromethyl)pyrrolidin-3-yl]carbamate. MS (ESI, m/z): 555 [M+H]⁺.

Step 5. 3-Amino-N-[(6S)-2-[(3R,4R)-3-amino-4-(fluoromethyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide

A solution of tert-butyl N-[(3R,4R)-1-[(6S)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-4-(fluoromethyl)pyrrolidin-3-yl]carbamate (15.0 mg, 0.027 mmol) and TFA (0.5 mL) in DCM (1.5 mL) was stirred for 25 min at 25° C. The resulting mixture was concentrated under vacuum. The residue was treated with a solution of NH₃ (1.0 mL, 7M in MeOH). The resulting solution was stirred for 30 min and then concentrated under vacuum. The residue was purified by prep-HPLC (Column:)(Bridge Prep OBD C18 Column, 30×150 mm 5 um; Mobile phase, A: water (containing 10 mmol/L NH₄HCO₃) and B: ACN (20% to 45% in 7 min)). The collected fraction was lyophilized to afford 3-amino-N-[(6S)-2-[(3R,4R)-3-amino-4-(fluoromethyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide as a white solid. MS (ESI, m/z): 455 [M+H]⁺. ¹H NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.31 (d, J=8.0 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.16 (br s, 2H), 6.23 (d, J=8.4 Hz, 1H), 4.81-4.47 (m, 2H), 4.11-4.09 (m, 1H), 3.61-3.60 (m, 1H), 3.54-3.46 (m, 2H), 3.33-3.28 (m, 1H), 3.20-3.18 (m, 1H), 2.81-2.68 (m, 4H), 2.59 (s, 3H), 2.02-1.96 (m, 1H), 1.90-1.66 (m, 2H).

Step 6. 3-Amino-N-[(6S)-2-[(3S,4S)-3-amino-4-(fluoromethyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide

A solution of tert-butyl N-[(3S,4S)-1-[(6S)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-4-(fluoromethyl)pyrrolidin-3-yl]carbamate (15.0 mg, 0.027 mmol) and TFA (0.5 mL) in DCM (1.5 mL) was stirred for 25 min at 25° C. The resulting mixture was concentrated under vacuum. NH₃ (1.0 mL, 7M in MeOH) was added to the residue. The resulting solution was stirred for 30 min and concentrated under vacuum. The residue was purified by prep-HPLC (Column:)(Bridge Prep OBD C18 Column, 30×150 mm Sum; Mobile phase, A: water (containing 10 mmol/L NH₄HCO₃) and B: ACN (20% to 45% in 7 min)). The collected fraction was lyophilized to afford 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-(fluoromethyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide as a white solid. MS (ESI, m/z): 455 [M+H]⁺. ¹H NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.31 (d, J=8.0 Hz, 1H), 7.58 (d, J=7.6 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.20 (d, J=8.8 Hz, 1H), 7.16 (br s, 2H), 6.23 (d, J=8.4 Hz, 1H), 4.81-4.47 (m, 2H), 4.12-4.09 (m, 1H), 3.61-3.60 (m, 1H), 3.53-3.47 (m, 2H), 3.33-3.27 (m, 1H), 3.21-3.18 (m, 1H), 2.81-2.68 (m, 4H), 2.59 (s, 3H), 2.02-1.96 (m, 1H), 1.90-1.66 (m, 2H).

Example 28-1. 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-(2-methoxyethoxy)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide and Example 28-2. 3-amino-N-[(6S)-2-[(3R,4R)-3-amino-4-(2-methoxyethoxy)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide

Step 1. trans-Benzyl N-[(6S)-2-(3-[[(tert-butoxy)carbonyl]amino]-4-(2-methoxyethoxy)pyrrolidin-1-yl)-5,6,7,8-tetrahydroquinolin-6-yl]carbamate

A mixture of benzyl N-[(6S)-2-(trifluoromethanesulfonyloxy)-5,6,7,8-tetrahydroquinolin-6-yl]carbamate (Intermediate 47-2) (200 mg, 0.465 mmol), trans-tert-butyl N-[4-(2-methoxyethoxy)pyrrolidin-3-yl]carbamate (Intermediate 55) (157 mg, 0.603 mmol), RuPhos Pd G3 (38.9 mg, 0.046 mmol), RuPhos (22.0 mg, 0.047 mmol) and Cs₂CO₃ (454 mg, 1.39 mmol) in toluene (4 mL) was stirred for 3 h at 100° C. After cooling to 26° C., the solids were filtered out. The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:1 ethyl acetate/pet. ether) to give trans-benzyl N-[(6S)-2-(3-[[(tert-butoxy)carbonyl]amino]-4-(2-methoxyethoxy)pyrrolidin-1-yl)-5,6,7,8-tetrahydroquinolin-6-yl]carbamate as a yellow solid. MS (ESI, m/z): 541 [M+H]⁺.

Step 2. trans-tert-Butyl N-[1-[(6S)-6-amino-5,6,7,8-tetrahydroquinolin-2-yl]-4-(2-methoxyethoxy)pyrrolidin-3-yl]carbamate

A mixture of trans-benzyl N-[(6S)-2-(3-[[(tert-butoxy)carbonyl]amino]-4-(2-methoxyethoxy)pyrrolidin-1-yl)-5,6,7,8-tetrahydroquinolin-6-yl]carbamate (140 mg, 0.259 mmol) and Palladium on carbon (70.0 mg, 10%) in ethyl acetate (10 mL) was stirred for 3 h at 26° C. under an atmosphere of hydrogen (balloon). The solids were filtered out. The filtrate was concentrated under vacuum to give trans-tert-butyl N-[1-[(6S)-6-amino-5,6,7,8-tetrahydroquinolin-2-yl]-4-(2-methoxyethoxy)pyrrolidin-3-yl]carbamate as a black solid. MS (ESI, m/z): 407 [M+H]⁺.

Step 3. trans-tert-Butyl N-[1-[(6S)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-4-(2-methoxyethoxy)pyrrolidin-3-yl]carbamate

HBTU (112 mg, 0.295 mmol) was added to a solution of trans-tert-butyl N-[1-[(6S)-6-amino-5,6,7,8-tetrahydroquinolin-2-yl]-4-(2-methoxyethoxy)pyrrolidin-3-yl]carbamate (100 mg, 0.246 mmol), Et₃N (0.103 mL, 0.741 mmol) and 3-amino-6-methylthieno[2,3-b]pyridine-2-carboxylic acid (61.0 mg, 0.293 mmol) in DMA (2 mL). The resulting solution was stirred for 1 h at 26° C. The mixture was purified reverse phase chromatography (Column: C₁₈ silica gel; Mobile phase, A: water (containing 0.05% TFA) and B: ACN (20% to 85% in 25 min)). The collected fraction was concentrated under vacuum to give trans-tert-butyl N-[1-[(6S)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-4-(2-methoxyethoxy)pyrrolidin-3-yl]carbamate as a yellow solid. MS (ESI, m/z): 597 [M+H]⁺.

Step 4. 3-Amino-N-[(6S)-2-[(3S,S-3-amino-4-(2-methoxyethoxy)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide and 3-Amino-N-[(6S)-2-[(3R,4R)-3-amino-4-(2-methoxyethoxy)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide

trans-tert-Butyl N-[1-[(6S)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-4-(2-methoxyethoxy)pyrrolidin-3-yl]carbamate (120 mg, 0.201 mmol) was separated by chiral HPLC (Column: Chiralpak IG, 2×25 cm, 5 μm; Mobile phase, A: hexanes:DCM=3:1 (0.1% Et₂NH) and B: EtOH (hold 40% in 20 min)). The first eluting isomer (RT=12.26 min) was collected and concentrated under vacuum to give a yellow solid, stereochemistry on the pyrrolidine arbitrarily assigned as 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-(2-methoxyethoxy)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide. The second eluting isomer (RT=17.55 min) was collected and concentrated under vacuum to give a yellow solid, stereochemistry on the pyrrolidine arbitrarily assigned as 3-amino-N-[(6S)-2-[(3R,4R)-3-amino-4-(2-methoxyethoxy)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide. MS (ESI, m/z): 597 [M+H]⁺.

Step 5. 3-Amino-N-[(6S)-2-[(3S,4S)-3-amino-4-(2-methoxyethoxy)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide

A solution of tert-butyl N-[(3S,4S)-1-[(6S)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-4-(2-methoxyethoxy)pyrrolidin-3-yl]carbamate (27.0 mg, 0.047 mmol) and TFA (1.00 mL) in DCM (3 mL) was stirred for 30 min at 26° C. The resulting mixture was concentrated under vacuum. The residue was treated with a solution of NH₃ (2.00 mL, 7M in MeOH). The resulting solution was stirred for 30 min, and then concentrated under vacuum. The residue was purified by prep-HPLC (Column: XBridge Prep OBD C18, 19×150 mm, 5 μm, 13 nm; Mobile phase, A: water (10 mM NH₄HCO₃) and B: ACN (18% to 40% in 8 min), Flow rate: 60 mL/min). The collected fraction was lyophilized to give 3-amino-N-[(65)-2-[(3S,4S)-3-amino-4-(2-methoxyethoxy)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide as a white solid. MS (ESI, m/z): 497 [M+H]⁺. ¹H NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.31 (d, J=8.4 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 7.17 (br s, 2H), 6.22 (d, J=8.4 Hz, 1H), 4.14-4.10 (m, 1H), 3.75-3.74 (m 1H), 3.64-3.55 (m, 3H), 3.49-3.31 (m, 5H), 3.24 (s, 3H), 3.14-3.12 (m, 1H), 2.82-2.72 (m, 4H), 2.59 (s, 3H), 2.03-1.82 (m, 4H).

Step 6. 3-amino-N-[(6S)-2-[(3R,4R)-3-amino-4-(2-methoxyethoxy)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide

A solution of tert-butyl N-[(3R,4R)-1-[(6S)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-4-(2-methoxyethoxy)pyrrolidin-3-yl]carbamate (26.0 mg, 0.045 mmol) and TFA (1.00 mL) in DCM (3 mL) was stirred for 30 min at 25° C. The resulting mixture was concentrated under vacuum. NH₃ (2.00 mL, 7M in MeOH) was added to the residue. The resulting solution was stirred for 30 min, and then concentrated under vacuum. The residue was purified by prep-HPLC (Column: X Bridge Prep OBD C18, 30×150 mm, 5 μm; Mobile phase, A: water (10 mM NH₄HCO₃) and B: ACN (18% to 40% in 8 min), Flow rate: 60 mL/min). The collected fraction was lyophilized to give 3-amino-N-[(65)-2-[(3R,4R)-3-amino-4-(2-methoxyethoxy)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide as a white solid. MS (ESI, m/z): 497 [M+H]⁺. ¹H NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.31 (d, J=8.4 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 7.17 (br s, 2H), 6.22 (d, J=8.4 Hz, 1H), 4.15-4.11 (m, 1H), 3.75-3.74 (m 1H), 3.63-3.59 (m, 3H), 3.48-3.33 (m, 5H), 3.24 (s, 3H), 3.14-3.11 (m, 1H), 2.80-2.72 (m, 4H), 2.59 (s, 3H), 2.01-1.82 (m, 4H).

Example 29-1. 3-Amino-N-[(6S)-2-[(9S)-9-amino-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide and Example 29-2. 3-Amino-N-[(6S)-2-[(9R)-9-amino-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide

Step 1. Benzyl N-[(6S)-2-(9-[[(tert-butoxy)carbonyl]amino]-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-5,6,7,8-tetrahydroquinolin-6-yl]carbamate

A mixture of benzyl N-[(6S)-2-(trifluoromethanesulfonyloxy)-5,6,7,8-tetrahydroquinolin-6-yl]carbamate (Intermediate 47-2) (180 mg, 0.410 mmol), tert-butyl N-[1,4-dioxa-7-azaspiro[4.4]nonan-9-yl]carbamate (Intermediate 59) (150 mg, 0.614 mmol), RuPhos (19.0 mg, 0.041 mmol), RuPhos Pd G3 (34.0 mg, 0.041 mmol) and Cs₂CO₃ (334 mg, 1.025 mmol) in toluene (10 mL) was stirred for 3 h at 95° C. The mixture was allowed to cool down to 25° C., filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:1 ethyl acetate/pet. ether) to afford benzyl N-[(6S)-2-(9-[[(tert-butoxy)carbonyl]amino]-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-5,6,7,8-tetrahydroquinolin-6-yl]carbamate as a white solid. MS (ESI, m/z): 525 [M+H]⁺.

Step 2. Tert-Butyl N-[7-[(6S)-6-amino-5,6,7,8-tetrahydroquinolin-2-yl]-1,4-dioxa-7-azaspiro[4.4]nonan-9-yl]carbamate

A mixture of benzyl N-[(6S)-2-(9-[[(tert-butoxy)carbonyl]amino]-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-5,6,7,8-tetrahydroquinolin-6-yl]carbamate (180 mg, 0.336 mmol) and Pd/C (180 mg, 10%) in ethyl acetate (5 mL) was stirred for 2 h at 25° C. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate (3×5 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl N-[7-[(65)-6-amino-5,6,7,8-tetrahydroquinolin-2-yl]-1,4-dioxa-7-azaspiro[4.4]nonan-9-yl]carbamate as a brown solid. MS (ESI, m/z): 391 [M+H]⁺.

Step 3. Tert-Butyl N-[7-[(6S)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-1,4-dioxa-7-azaspiro[4.4]nonan-9-yl]carbamate

HBTU (114 mg, 0.301 mmol) was added to a solution of tert-butyl N-[7-[(6S)-6-amino-5,6,7,8-tetrahydroquinolin-2-yl]-1,4-dioxa-7-azaspiro[4.4]nonan-9-yl]carbamate (100 mg, 0.251 mmol), 3-amino-6-methylthieno[2,3-b]pyridine-2-carboxylic acid (57.0 mg, 0.274 mmol) and Et₃N (0.104 mL, 0.751 mmol) in DMA (3 mL). The reaction was stirred for 3 h at 25° C. The residue was purified by reverse phase chromatography (Column: C₁₈ silica gel; Mobile phase, A: water (containing 0.1% TFA) and B: ACN (0% to 60% in 30 min)) to afford tert-butyl N-[7-[(6S)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-1,4-dioxa-7-azaspiro[4.4]nonan-9-yl]carbamate as a yellow solid. MS (ESI, m/z): 581 [M+H]⁺.

Step 4. Tert-Butyl N-[(9S)-7-[(6S)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-1,4-dioxa-7-azaspiro[4.4]nonan-9-yl]carbamate and tert-Butyl N-[(9R)-7-[(6S)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-1,4-dioxa-7-azaspiro[4.4]nonan-9-yl]carbamate

tert-Butyl N-[7-[(6S)-6-[3-amino-6-methylthieno[2,3]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-1,4-dioxa-7-azaspiro[4.4]nonan-9-yl]carbamate (100 mg, 0.169 mmol) was separated by chiral HPLC (Column: Chiralpak IF, 2×25 cm, 5 μm; Mobile phase, A: MTBE (0.1% Et₂NH) and B: EtOH (hold 30% in 24 min); Flow rate: 12 mL/min). The first eluting isomer (RT=15.97 min) was collected and concentrated under vacuum to afford a yellow solid, stereochemistry on the pyrrolidine arbitrarily assigned as tert-butyl N-[(9S)-7-[(6S)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-1,4-dioxa-7-azaspiro[4.4]nonan-9-yl]carbamate. MS (ESI, m/z): 581 [M+H]⁺.

The second eluting isomer (RT=20.62 min) was collected and concentrated under vacuum to afford a yellow solid, stereochemistry on the pyrrolidine arbitrarily assigned as tert-butyl N-[(9R)-7-[(6S)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-1,4-dioxa-7-azaspiro[4.4]nonan-9-yl]carbamate. MS (ESI, m/z): 581 [M+H]⁺.

Step 5. 3-Amino-N-[(6S)-2-[(9S)-9-amino-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide

A solution of tert-butyl N-[(95)-7-[(65)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-1,4-dioxa-7-azaspiro[4.4]nonan-9-yl]carbamate (40 mg, 0.068 mmol) and TFA (0.50 mL) in DCM (1.5 mL) was stirred for 30 min at 25° C. The resulting solution was concentrated under vacuum. NH₃ (2.0 mL, 7M in MeOH) was added to the residue. The resulting solution was stirred for 30 min at 25° C., and then was concentrated under vacuum. The residue was purified by prep-HPLC (Column: X Bridge Prep C18 OBD, 19×150 mm, 5 μm; Mobile phase, A: water (0.05% NH₄HCO₃) and B: ACN (20% to 35% in 7 min)). The collected fraction was lyophilized to afford 3-amino-N-[(6S)-2-[(9S)-9-amino-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide as a white solid. MS (ESI, m/z): 481 [M+H]⁺. ¹H-NMR (CDCl₃, 400 MHz) δ (ppm): 7.82 (d, J=8.0 Hz, 1H), 7.22-7.20 (m, 1H), 6.20 (d, J=8.0 Hz, 1H), 6.06-6.02 (m, 2H), 5.52 (d, J=7.2 Hz, 1H), 4.48-4.42 (m, 1H), 4.14-4.09 (m, 4H), 3.82-3.69 (m, 2H), 3.53-3.50 (m, 2H), 3.24-3.20 (m, 1H), 3.09-3.08 (m, 1H), 2.94-2.86 (m, 2H), 2.70-2.64 (m, 4H), 2.26-2.23 (m, 1H), 1.98-1.91 (m, 1H).

Step 6. 3-Amino-N-[(6S)-2-[(9R)-9-amino-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide

A solution of tert-butyl N-[(9R)-7-[(6S)-6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinolin-2-yl]-1,4-dioxa-7-azaspiro[4.4]nonan-9-yl]carbamate (40.0 mg, 0.068 mmol) and TFA (0.50 mL) in DCM (1.5 mL) was stirred for 30 min at 25° C. The resulting solution was concentrated under vacuum. NH₃ (2.0 mL, 7M in MeOH) was added to the residue. The resulting solution was stirred for 30 min at 25° C., and then was concentrated under vacuum. The residue was purified by prep-HPLC (Column: XBridge Prep C18 OBD, 19×150 mm, 5 μm; Mobile phase, A: water (0.05% NH₄HCO₃) and B: ACN (20% to 35% in 7 min)). The collected fraction was lyophilized to afford 3-amino-N-[(6S)-2-[(9R)-9-amino-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide as a white solid. MS (ESI, m/z): 481 [M+H]⁺. ¹H-NMR (CDCl₃, 400 MHz) δ (ppm): 7.82 (d, J=8.4 Hz, 1H), 7.22-7.20 (m, 1H), 6.20 (d, J=8.4 Hz, 1H), 6.06-6.00 (m, 2H), 5.53 (d, J=6.8 Hz, 1H), 4.48-4.42 (m, 1H), 4.14-4.09 (m, 4H), 3.82-3.67 (m, 2H), 3.53-3.501 (m, 2H), 3.27-3.22 (m, 1H), 3.10-3.08 (m, 1H), 2.95-2.90 (m, 2H), 2.70-2.65 (m, 4H), 2.24-2.20 (m, 1H), 1.93-1.87 (m, 1H).

Example 30-1. 3-Amino-N-[(6S)-3-fluoro-2-(piperazin-1-yl)-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide and Example 30-2. 3-Amino-N-[(6R)-3-fluoro-2-(piperazin-1-yl)-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide

Step 1. Tert-Butyl 4-(6-[[(benzyloxy)carbonyl]amino]-5,6,7,8-tetrahydroquinolin-2-yl)piperazine-1-carboxylate

A mixture of benzyl N-[2-[(trifluoromethane)sulfonyloxy]-5,6,7,8-tetrahydroquinolin-6-yl]carbamate (Intermediate 47-1) (400 mg, 0.930 mmol), tert-butyl piperazine-1-carboxylate (208 mg, 1.12 mol), RuPhos (87.0 mg, 0.190 mmol), RuPhos Pd G3 (76.0 mg, 0.090 mmol), and Cs₂CO₃ (758 mg, 2.33 mmol) in toluene (15 mL) was stirred for 3 h at 95° C. After cooling to 25° C., the solid was filtered out. The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:3 ethyl acetate/pet. ether) to afford tert-butyl 4-(6-[[(benzyloxy)carbonyl]amino]-5,6,7,8-tetrahydroquinolin-2-yl)piperazine-1-carboxylate as a white solid. MS (ESI, m/z): 467 [M+H]⁺.

Step 2. Tert-Butyl 4-(6-[[(benzyloxy)carbonyl]amino]-3-fluoro-5,6,7,8-tetrahydroquinolin-2-yl)piperazine-1-carboxylate

A solution of SelectFluor (683 mg, 1.93 mmol) in ACN (10 mL) was added to a stirring solution of tert-butyl 4-(6-[[(benzyloxy)carbonyl]amino]-5,6,7,8-tetrahydroquinolin-2-yl)piperazine-1-carboxylate (600 mg, 1.29 mmol) in DCM (30 mL) and MeOH (30 mL). The resulting solution was stirred for 1 h at −20° C. The resulting mixture was concentrated under vacuum. The residue was purified by prep-HPLC (Column: XBridge Prep C18 OBD, 5 μm, 19×150 mm; Mobile Phase, A: water (0.05% TFA) and B: ACN (55% to 85% in 7 min)). The collected fraction was concentrated under vacuum to give tert-butyl 4-(6-[[(benzyloxy)carbonyl]amino]-3-fluoro-5,6,7,8-tetrahydroquinolin-2-yl)piperazine-1-carboxylate as an off-white solid. MS (ESI, m/z):485 [M+H]⁺.

Step 3. Tert-Butyl 4-(6-amino-3-fluoro-5,6,7,8-tetrahydroquinolin-2-yl)piperazine-1-carboxylate

A mixture of tert-butyl 4-(6-[[(benzyloxy)carbonyl]amino]-3-fluoro-5,6,7,8-tetrahydroquinolin-2-yl)piperazine-1-carboxylate (70.0 mg, 0.140 mmol) and palladium on carbon (70.0 mg, 10%) in ethyl acetate (5 mL) was stirred for 1 h at 25° C. under hydrogen atmosphere (balloon). The solids were filtered out. The filtrate was concentrated under vacuum to give tert-butyl 4-(6-amino-3-fluoro-5,6,7,8-tetrahydroquinolin-2-yl)piperazine-1-carboxylate as an off-white solid. MS (ESI, m/z): 351 [M+H]⁺.

Step 4. Tert-Butyl 4-(6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-3-fluoro-5,6,7,8-tetrahydroquinolin-2-yl)piperazine-1-carboxylate

HBTU (58.0 mg, 0.150 mmol) was added to a solution of 4-(6-amino-3-fluoro-5,6,7,8-tetrahydroquinolin-2-yl)piperazine-1-carboxylate (45.0 mg, 0.130 mmol), 3-amino-6-methylthieno[2,3-b]pyridine-2-carboxylic acid (32.0 mg, 0.150 mmol) and Et₃N (54.0 μL, 0.390 mmol) in DMA (2 mL). The resulting solution was stirred for 30 min at 25° C. The mixture was purified via reverse phase chromatography (Column: C₁₈ silica gel; Mobile phase, A: water (containing 10 mmoL/L NH₄HCO₃) and B: ACN (0% to 85% within 25 min)). The collected fraction was concentrated under vacuum to give tert-butyl 4-(6-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-3-fluoro-5,6,7,8-tetrahydroquinolin-2-yl)piperazine-1-carboxylate as an off-white solid. MS (ESI, m/z): 541 [M+H]⁺.

Step 5. 3-Amino-N-[(6S)-3-fluoro-2-(piperazin-1-yl)-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide and 3-Amino-N-[(6R)-3-fluoro-2-(piperazin-1-yl)-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide

A solution of tert-butyl 4-[3-amino-6-(3-amino-6-methyl-1-benzothiophene-2-amido)-5,6,7,8-tetrahydroquinolin-2-yl]piperazine-1-carboxylate (40.0 mg, 0.070 mmol) and TFA (1.00 mL) in DCM (3 mL) was stirred for 1 h at 25° C. The resulting mixture was concentrated under vacuum to give TFA salt of 3-amino-N-[3-fluoro-2-(piperazin-1-yl)-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide as a yellow solid. The enantiomers were separated by chiral HPLC (Column: Chiralpak IC, 2×25 cm, 5 μm; Mobile Phase, A: Hex (0.2% Et₂NH) and B: EtOH (hold 50% in 20 min); Flow rate: 15 mL/min). The first eluting isomer (RT=11.3 min) was concentrated under vacuum and then lyophilized to afford an off-white solid, stereochemistry arbitrarily assigned as 3-amino-N-[(6S)-3-fluoro-2-(piperazin-1-yl)-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide. MS (ESI, m/z): 441 [M+H]⁺. ¹H-NMR (DMSO-d₆, 300 MHz) δ (ppm): 8.30 (d, J=8.4 Hz, 1H), 7.60 (d, J=7.5 Hz, 1H), 7.32-7.22 (m, 2H), 7.16 (br s, 2H), 4.14 (br s, 1H), 3.25-3.21 (m, 4H), 2.83-2.72 (m, 8H), 2.58 (s, 3H), 1.98-1.86 (m, 2H).

The second eluting isomer (RT=16.9 min) was concentrated under vacuum and then lyophilized with ACN and water to afford an off-white solid, stereochemistry arbitrarily assigned as 3-amino-N-[(6R)-3-fluoro-2-(piperazin-1-yl)-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide. MS (ESI, m/z): 441 [M+H]⁺. ¹H-NMR (DMSO-d₆, 300 MHz) δ (ppm): 8.30 (d, J=8.1 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.32-7.21 (m, 2H), 7.16 (br s, 2H), 4.15 (br s, 1H), 3.22-3.20 (m, 4H), 2.83-2.72 (m, 8H), 2.58 (s, 3H), 2.07-1.83 (m, 2H).

Example 31-1. 3-Amino-N-[(6S)-2-[(3S,4S)-3-amino-4-(propan-2-yloxy)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinazolin-6-yl]-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide and Example 31-2. 3-Amino-N-[(6R)-2-[(3S,4S)-3-amino-4-(propan-2-yloxy)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinazolin-6-yl]-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide

Step 1. Benzyl N-[2-[(3S,4S)-3-[[(tert-butoxy)carbonyl]amino]-4-(propan-2-yloxy)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinazolin-6-yl]carbamate

A solution of benzyl N-(2-chloro-5,6,7,8-tetrahydroquinazolin-6-yl)carbamate (Intermediate 57) (300 mg, 0.944 mmol), tert-butyl N-[(3S,4S)-4-(propan-2-yloxy)pyrrolidin-3-yl]carbamate (Intermediate 56) (276 mg, 1.133 mmol) and DIEA (0.312 mL, 1.89 mmol) in DMA (10 mL) was microwaved for 1 h at 150° C. After cooling to 25° C., the residue was purified by reverse phase chromatography (Column: C₁₈ silica gel; Mobile phase, A: water (containing 10 mmol/L NH₄HCO₃) and B: ACN (0% to 70% in 20 min)). The collected fraction was concentrated under vacuum to afford benzyl N-[2-[(3S,4S)-3-[[(tert-butoxy)carbonyl]amino]-4-(propan-2-yloxy)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinazolin-6-yl]carbamate as a brown solid. MS (ESI, m/z): 526 [M+H]⁺.

Step 2. Tert-Butyl N-[(3S,4S)-1-(6-amino-5,6,7,8-tetrahydroquinazolin-2-yl)-4-(propan-2-yloxy)pyrrolidin-3-yl]carbamate

A mixture of benzyl N-[2-[(3S,4S)-3-[[(tert-butoxy)carbonyl]amino]-4-(propan-2-yloxy)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinazolin-6-yl]carbamate (300 mg, 0.542 mmol) and Palladium on carbon (300 mg, 10%) in ethyl acetate (20 mL) was stirred for 2 h at 20° C. under hydrogen atmosphere (balloon). The resulting mixture was filtered and the filter cake was washed with ethyl acetate (3×10 mL). The filtrate was concentrated under vacuum to afford tert-butyl N-[(3S,4S)-1-(6-amino-5,6,7,8-tetrahydroquinazolin-2-yl)-4-(propan-2-yloxy)pyrrolidin-3-yl]carbamate as a brown solid. MS (ESI, m/z): 392 [M+H]⁺.

Step 3. Tert-Butyl N-[(3S,4S)-1-[6-[3-amino-4,6-dimethylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinazolin-2-yl]-4-(propan-2-yloxy)pyrrolidin-3-yl]carbamate

HBTU (140 mg, 0.370 mmol) was added to a solution of tert-butyl N-[(3S,4S)-1-(6-amino-5,6,7,8-tetrahydroquinazolin-2-yl)-4-(propan-2-yloxy)pyrrolidin-3-yl]carbamate (100 mg, 0.230 mmol), Et₃N (0.096 mL, 0.690 mmol) and 3-amino-4,6-dimethylthieno[2,3-b]pyridine-2-carboxylic acid (Intermediate 21) (70.0 mg, 0.300 mmol) in DMA (3 mL). The resulting solution was stirred for 3 h at 25° C. The residue was purified by reverse phase chromatography (Column: C₁₈ silica gel; Mobile phase, A: water (containing 10 mmol/L NH₄HCO₃) and B: ACN (10% to 60% in 30 min)). The collected fraction was concentrated to give tert-butyl N-[(3S,4S)-1-[6-[3-amino-4,6-dimethylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinazolin-2-yl]-4-(propan-2-yloxy)pyrrolidin-3-yl]carbamate as a white solid. MS (ESI, m/z): 596 [M+H]⁺.

Step 4. Tert-Butyl N-[(3S,4S)-1-[(6S)-6-[3-amino-4,6-dimethylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinazolin-2-yl]-4-(propan-2-yloxy)pyrrolidin-3-yl]carbamate and tert-Butyl N-[(3S,4S)-1-[(6R)-6-[3-amino-4,6-dimethylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinazolin-2-yl]-4-(propan-2-yloxy)pyrrolidin-3-yl]carbamate

tert-Butyl N-[(3S,4S)-1-[6-[3-amino-4,6-dimethylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinazolin-2-yl]-4-(propan-2-yloxy)pyrrolidin-3-yl]carbamate (65.0 mg, 0.109 mmol) was separated by chiral HPLC (Column: Chiralpak IA, 2×25 cm, 5 μm; Mobile phase, A: hexanes:DCM=3:1 and B: EtOH (hold 50% in 19 min); Flow rate: 16 mL/min). The first eluting isomer (RT=11.42 min) was collected and concentrated to give a white solid, stereochemistry of the amide arbitrarily assigned as tert-butyl N-[(3S,4S)-1-[(6S)-6-[3-amino-4,6-dimethylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinazolin-2-yl]-4-(propan-2-yloxy)pyrrolidin-3-yl]carbamate. The second eluting isomer (RT=15.96 min) was collected and concentrated under vacuum to give a white solid, stereochemistry of the amide arbitrarily assigned as tert-butyl N-[(3S,4S)-1-[(6R)-6-[3-amino-4,6-dimethylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinazolin-2-yl]-4-(propan-2-yloxy)pyrrolidin-3-yl]carbamate. MS (ESI, m/z): 596 [M+H]⁺.

Step 5. 3-Amino-N-[(6S)-2-[(3S,4S)-3-amino-4-(propan-2-yloxy)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinazolin-6-yl]-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide

A solution of tert-butyl N-[(3S,4S)-1-[(6S)-6-[3-amino-4,6-dimethylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinazolin-2-yl]-4-(propan-2-yloxy)pyrrolidin-3-yl]carbamate (28.0 mg, 0.05 mmol) and TFA (0.5 mL) in DCM (1.5 mL) was stirred for 30 min at 25° C. The resulting mixture was concentrated under vacuum. The residue was treated with a solution of NH₃ (1.0 mL, 7M in MeOH). The resulting solution was stirred for 30 min and concentrated under vacuum. The residue was purified by prep-HPLC (Column: XBridge Shield RP18 OBD, 30×150 mm, 5 μm; Mobile phase, A: water (10 mM NH₄HCO₃) and B: ACN (25% to 45% in 7 min); Flow rate: 60 mL/min). The collected fraction was lyophilized to give 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-(propan-2-yloxy)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinazolin-6-yl]-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide as a white solid. MS (ESI, m/z): 496 [M+H]⁺. ¹H NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.06 (s, 1H), 7.64 (br s, 1H), 7.04 (s, 1H), 6.82 (br s, 2H), 4.14-4.11 (m, 1H), 3.78-3.73 (m, 1H), 3.71-3.70 (m, 2H), 3.57-3.53 (m, 1H), 3.37-3.32 (m, 5H), 3.25-3.22 (m, 1H), 2.82-2.62 (m, 7H), 2.01-1.98 (m, 1H), 1.91-1.83 (m, 1H), 1.74 (br s, 2H), 1.12-1.08 (m, 6H).

Step 6. 3-Amino-N-[(6R)-2-[(3S,4S)-3-amino-4-(propan-2-yloxy)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinazolin-6-yl]-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide

A solution of tert-butyl N-[(3S,4S)-1-[(6R)-6-[3-amino-4,6-dimethylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroquinazolin-2-yl]-4-(propan-2-yloxy)pyrrolidin-3-yl]carbamate (27.0 mg, 0.05 mmol) and TFA (0.5 mL) in DCM (1.5 mL) was stirred for 30 min at 25° C. The resulting mixture was concentrated under vacuum. NH₃ (1.0 mL, 7M in MeOH) was added to the residue. The resulting solution was stirred for 30 min and concentrated under vacuum.

The residue was purified by prep-HPLC (Column: XBridge Shield RP18 OBD, 30×150 mm, 5 μm; Mobile phase, A: water (10 mM NH₄HCO₃) and B: ACN (25% to 50% in 7 min); Flow rate: 60 mL/min). The collected fraction was lyophilized to give 3-amino-N-[(6R)-2-[(3S,4S)-3-amino-4-(propan-2-yloxy)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinazolin-6-yl]-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide as a white solid. MS (ESI, m/z): 496 [M+H]⁺. ¹H NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.07 (s, 1H), 7.65 (br s, 1H), 7.05 (s, 1H), 6.83 (br s, 2H), 4.16-4.13 (m, 1H), 3.79-3.74 (m, 1H), 3.72-3.71 (m, 2H), 3.57-3.53 (m, 1H), 3.38-3.33 (m, 5H), 3.26-3.23 (m, 1H), 2.83-2.62 (m, 7H), 2.01-1.99 (m, 1H), 1.92-1.83 (m, 1H), 1.74 (br s, 2H), 1.12-1.08 (m, 6H).

The following examples in Table 22 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Examples 31-1 and 31-2.

TABLE 22 LRMS Example m/z Number Structure and Compound Name [M + H]⁺ ¹H NMR 31-3¹

3-amino-6-methyl-N-[(6′S)-2′- (piperazin-1-yl)-6′,7′-dihydro-5′H- spiro[cyclopropane-1,8′-quinoline]-6′- yl]thieno[2,3-b]pyridine-2- carboxamide 449 (DMSO-d6, 400 MHz) δ (ppm): 8.31 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.16 (br s, 2H), 6.58-6.51 (m, 1H), 4.33-4.27 (m, 1H), 3.44-3.27 (m, 4H), 2.88-2.82 (m, 2H), 2.75-2.68 (m, 4H), 2.59 (s, 3H), 2.39 (br s, 1H), 2.29-2.22 (m, 1H), 1.53-1.45 (m, 2H), 0.92-0.86 (m, 1H), 0.71-0.69 (m, 2H). 31-4¹

3-amino-6-methyl-N-[(6′R)-2′- (piperazin-1-yl)-6′,7′-dihydro-5′H- spirocyclopropane-1,8′-quinoline]-6′- yl]thieno[2,3-b]pyridine-2- carboxamide 449 (DMSO-d6, 400 MHz) δ (ppm): 8.31 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.16 (br s, 2H), 6.52 (d, J = 8.4 Hz, 1H), 4.32- 4.28 (m, 1H), 3.43-3.28 (m, 4H), 2.88-2.82 (m, 2H), 2.75-2.64 (m, 4H), 2.59 (s, 3H), 2.39-2.34 (m, 1H), 2.29- 2.22 (m, 1H), 1.53-1.40 (m, 2H), 0.92-0.86 (m, 1H), 0.71-0.69 (m, 2H). ¹Notes on procedures: In Step 1, the triflate Intermediate 47-4 was used. In Step 4, the enantiomers were separated by chiral HPLC using the column Chiralpak IC and Mobile Phase 10% EtOH/MTBE (containing 10 mmol/L NH₃ in MeOH) to afford the precursor to Example 31-3 as the first eluted isomer (stereochemistry arbitrarily assigned); and the precursor to Example 31-4 as the second eluted isomer (stereochemistry arbitrarily assigned).

Example 32-1. 3-Amino-6-methyl-N-[(7S)-3-(piperazin-1-yl)-5,6,7,8-tetrahydroisoquinolin-7-yl]thieno[2,3-b]pyridine-2-carboxamide and Example 32-2. 3-Amino-6-methyl-N-[(7R)-3-(piperazin-1-yl)-5,6,7,8-tetrahydroisoquinolin-7-yl]thieno[2,3-b]pyridine-2-carboxamide

Step 1. Tert-Butyl 4-(7-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroisoquinolin-3-yl)piperazine-1-carboxylate

HBTU (70.0 mg, 0.180 mmol) was added to a solution of tert-butyl 4-(7-amino-5,6,7,8-tetrahydroisoquinolin-3-yl)piperazine-1-carboxylate (Intermediate 58) (30 mg, 0.090 mmol), 3-amino-6-methylthieno[2,3-b]pyridine-2-carboxylic acid (20.0 mg, 0.100 mmol) and Et³N (0.038 mL, 0.270 mmol) in DMA (2 mL). The resulting solution was stirred for 30 min at 25° C. The mixture was purified via reverse phase chromatography (Column: X Bridge C18, 19×150 mm, 5 um; Mobile Phase, A: water (containing 10 mmol/L NH₄HCO₃) and B: ACN (10% to 80% in 30 min)). The collected fraction was concentrated under vacuum to give tert-butyl 4-(7-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroisoquinolin-3-yl)piperazine-1-carboxylate as a white solid. MS (ESI, m/z): 523 [M+H]⁺.

Step 2. 3-Amino-6-methyl-N-[3-(piperazin-1-yl)-5,6,7,8-tetrahydroisoquinolin-7-yl]thieno[2,3-b]pyridine-2-carboxamide

A solution of tert-butyl 4-(7-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,7,8-tetrahydroisoquinolin-3-yl)piperazine-1-carboxylate (35.0 mg, 0.070 mmol) and TFA (0.50 mL) in DCM (1.50 mL) was stirred for 30 min at 25° C. The reaction mixture was concentrated under vacuum. Then a solution of NH₃ (2 mL, 7M in methanol) was added. The resulting solution was stirred for 30 min at 25° C. The resulting solution was concentrated under vacuum to give 3-amino-6-methyl-N-[3-(piperazin-1-yl)-5,6,7,8-tetrahydroisoquinolin-7-yl]thieno[2,3-b]pyridine-2-carboxamide as a white solid. MS (ESI, m/z): 423 [M+H]⁺.

Step 3. 3-Amino-6-methyl-N-[(7S)-3-(piperazin-1-yl)-5,6,7,8-tetrahydroisoquinolin-7-yl]thieno[2,3-b]pyridine-2-carboxamide and 3-Amino-6-methyl-N-[(7R)-3-(piperazin-1-yl)-5,6,7,8-tetrahydroisoquinolin-7-yl]thieno[2,3-b]pyridine-2-carboxamide

The racemate 3-amino-6-methyl-N-[3-(piperazin-1-yl)-5,6,7,8-tetrahydroisoquinolin-7-yl]thieno[2,3-b]pyridine-2-carboxamide (25.0 mg, 0.059 mmol) was separated into its enantiomers by chiral HPLC (Column: Chiralpak IG, 2×25 cm, 5 um; Mobile phase, A: MTBE (containing 0.1% Et₂NH) and B: ethanol (hold 50% in 20 min)). The first eluting isomer (RT=12.37 min) was concentrated under vacuum and then lyophilized to give a white solid, stereochemistry arbitrarily assigned as 3-amino-6-methyl-N-[(75)-3-(piperazin-1-yl)-5,6,7,8-tetrahydroisoquinolin-7-yl]thieno[2,3-b]pyridine-2-carboxamide. MS (ESI, m/z): 423 [M+H]⁺. ¹H NMR (CD₃OD, 400 MHz) δ (ppm): 8.22 (d, J=8.0 Hz, 1H), 7.89 (s, 1H), 7.33 (d, J=8.0 Hz, 1H), 6.63 (s, 1H), 4.25-4.23 (m, 1H), 3.49-3.43 (m, 4H), 3.06-2.98 (m, 1H), 2.97-2.92 (m, 6H), 2.82-2.69 (m, 1H), 2.66 (s, 3H), 2.15-2.13 (m, 1H), 1.89-1.81 (m, 1H). The second eluting isomer (RT=17.03 min) was concentrated under vacuum and then lyophilized to give a white solid, stereochemistry arbitrarily assigned as 3-amino-6-methyl-N-[(7R)-3-(piperazin-1-yl)-5,6,7,8-tetrahydroisoquinolin-7-yl]thieno[2,3-b]pyridine-2-carboxamide. MS (ESI, m/z): 423 [M+H]⁺. ¹H NMR (CD₃OD, 400 MHz) δ (ppm): 8.22 (d, J=8.0 Hz, 1H), 7.89 (s, 1H), 7.33 (d, J=8.0 Hz, 1H), 6.63 (s, 1H), 4.25-4.23 (m, 1H), 3.49-3.43 (m, 4H), 3.15-2.98 (m, 1H), 2.97-2.93 (m, 6H), 2.82-2.72 (m, 1H), 2.76 (s, 3H), 2.15-2.13 (m, 1H), 1.89-1.81 (m, 1H).

Example 33-1. (R)-3-amino-N-(5-fluoro-7-(piperazin-1-yl)chroman-3-yl-4,4-d2)-6-methylthieno[2,3-b]pyridine-2-carboxamide Example 33-2. (S)-3-amino-N-(5-fluoro-7-(piperazin-1-yl)chroman-3-yl-4,4-d2)-6-methylthieno[2,3-b]pyridine-2-carboxamide

Step 1. 3-Amino-N-(7-bromo-5-fluorochroman-3-yl-4,4-d2)-6-methylthieno[2,3-b]pyridine-2-carboxamide

A solution of 7-bromo-5-fluorochroman-4,4-d2-3-amine (Intermediate 5-2) (340 mg, 1.370 mmol), 3-amino-6-methylthieno[2,3-b]pyridine-2-carboxylic acid (342 mg, 1.645 mmol), Et₃N (0.287 ml, 2.056 mmol), and HBTU (624 mg, 1.645 mmol) in DMA (5 mL) was stirred at room temperature for 4 h. The reaction was reduced in volume by half under reduced pressure. EtOAc (5 mL) and H₂O (3 mL) were added. The organic layer was separated, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with 2% to 100% EtOAc/hexanes). Desired fractions were combined and concentrated to afford 3-amino-N-(7-bromo-5-fluorochroman-3-yl-4,4-d2)-6-methylthieno[2,3-b]pyridine-2-carboxamide as a yellow solid. MS: (ESI, m/z): 438 [M+H]⁺. ¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.61-7.83 (m, 1H), 7.03-7.13 (m, 1H), 6.69-6.90 (m, 2H), 6.00 (br s, 2H), 5.59 (br d, J=6.7 Hz, 1H), 4.47-4.82 (m, 1H), 3.95-4.29 (m, 3H), 2.85-2.86 (m, 1H), 2.67-2.79 (m, 3H), 2.59 (d, J=3.2 Hz, 3H).

Step 2. Tert-Butyl 4-(3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-5-fluorochroman-7-yl-4,4-d2)piperazine-1-carboxylate

A solution of 3-amino-N-(7-bromo-5-fluorochroman-3-yl-4,4-d2)-6-methylthieno[2,3-b]pyridine-2-carboxamide (150 mg, 0.342 mmol) was combined with tert-butyl piperazine-1-carboxylate (127 mg, 0.684 mmol) in anhydrous DMA (3.42 mL). A 1M in THF solution of LiHMDS (3.42 mL, 3.42 mmol) was added and the reaction was flushed with Na for 20 min. Pd-PEPPSI-IPent (34.2 mg, 0.034 mmol) was added and the reaction was stirred at 60° C. for 16 h. The reaction was diluted with 10 mL of EtOAc and washed with 3 mL of H₂O. The organic layer was separated, dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with 5% to 80% EtOAc/hexanes). Desired fractions were combined and concentrated to afford tert-butyl 4-(3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-5-fluorochroman-7-yl-4,4-d2)piperazine-1-carboxylate as an off-white solid. MS: (ESI, m/z): 544 [M+H]⁺.

Step 3. 3-Amino-N-(5-fluoro-7-(piperazin-1-yl)chroman-3-yl-4,4-d2)-6-methylthieno[2,3-b]pyridine-2-carboxamide

HCl (4M in 1,4-dioxane, 0.276 mL, 1.104 mmol) was added to a suspension of tert-butyl 4-(3-(3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamido)-5-fluorochroman-7-yl-4,4-d2)piperazine-1-carboxylate in EtOAc (1 mL). The reaction was stirred at 22° C. for 16 h. The reaction was concentrated to dryness under vacuum. The residue was purified by chiral HPLC using chiral column Chiralpak IA (Mobile Phase A: hexanes (0.1% Et₂NH), and B: EtOH (0.1% Et₂NH); 50% B) to afford Peak 1 whose stereochemistry was arbitrarily assigned as (R)-3-amino-N-(5-fluoro-7-(piperazin-1-yl)chroman-3-yl-4,4-d2)-6-methylthieno[2,3-b]pyridine-2-carboxamide and Peak 2 whose stereochemistry was arbitrarily assigned as (S)-3-amino-N-(5-fluoro-7-(piperazin-1-yl)chroman-3-yl-4,4-d2)-6-methylthieno[2,3-b]pyridine-2-carboxamide. MS: (ESI, m/z): 444 [M+H]⁺.

The following examples in Table 23 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Examples 33-1 and 33-2.

TABLE 23 LRMS Example m/z Number Structure and Compound Name [M + H]⁺ ¹H NMR 33-3¹

3-amino-N-[(3R)-7-[(1R,6S)-3,8- diazabicyclo[4.2.0]octan-8-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2- carboxamide 450 (DMSO-d6, 400 MHz) δ (ppm): 8.31 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.21 (br s, 2H), 6.87 (d, J = 8.4 Hz, 1H), 6.09-6.06 (m, 1H), 5.90 (s, 1H), 4.29-4.26 (m, 1H), 4.16-4.12 (m, 1H), 3.82-3.75 (m, 2H), 3.65-3.45 (m, 2H), 3.32-3.18 (m, 1H), 3.08-3.05 (m, 1H), 2.89-2.82 (m, 4H), 2.59 (s, 3H), 2.44- 2.38 (m, 1H), 1.92-1.88 (m, 1H), 1.80-1.63 (m, 1H). 33-4¹

3-amino-N-[(3R)-7-[(1S,6R)-3,8- diazabicyclo[4.2.0]octan-8-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2- carboxamide 450 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.21 (br s, 2H), 6.87 (d, J = 8.0 Hz, 1H), 6.10-6.07 (m, 1H), 5.91 (s, 1H), 4.27-4.25 (m, 1H), 4.16-4.13 (m, 1H), 3.82-3.77 (m, 2H), 3.65-3.47 (m, 2H), 3.32-3.30 (m, 1H), 3.09-3.06 (m, 1H), 2.91-2.84 (m, 4H), 2.59 (s, 3H), 2.45- 2.40 (m, 1H), 1.93-1.89 (m, 1H), 1.70- 1.61 (m, 1H). ¹Notes on procedures: In Step 1, 7-bromochroman-3-amine was used as the amine coupling partner to afford the racemate 3-amino-N-(7-bromochroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide. The enantiomers were separated by SFC using the chiral column ChiralArt Amylose-SA and Mobile Phase, A: CO₂, 65% and B: EtOH:DCM = 1:1 to afford (R)-3-amino-N-(7-bromochroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide as the first eluted isomer and (S)-3-amino-N-(7-bromochroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide as the second eluted isomer. In Step 2, cis-tert-butyl 3,8-diazabicyclo[4.2.0]octane-3-carboxylate was used as the amine coupling partner to afford cis-tert-butyl 8-[(3R)-3-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-3,4-dihydro-2H-1-benzopyran-7-yl]-3,8-diazabicyclo[4.2.0]octane-3-carboxylate. The cis isomers were separated by chiral HPLC using the chiral column Chiralpak IE and mobile phase 10% EtOH/MTBE (0.1% Et₂NH) to afford the precursor to Example 33-3 as the first eluted isomer (stereochemistry arbitrarily assigned) and the precursor to Example 33-4 as the second eluted isomer (stereochemistry arbitrarily assigned). In Step 3, boc-deprotection was accomplished by treatment with TFA in DCM.

Example 34. 3-Amino-N-[(3R)-7-(4-cyano-1,1-dioxo-1λ6-thian-4-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide

Step 1. Benzyl N-[(3R)-7-(4-hydroxythian-4-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]carbamate

n-BuLi (4.40 mL, 2.5 M in n-hexane) was added to a solution of benzyl (R)-(7-bromochroman-3-yl)carbamate (Intermediate 2) (800 mg, 2.16 mmol) in THF (20 mL) at −78° C. The resulting solution was stirred for 30 min at −78° C. Then a solution of thian-4-one (1.28 g, 11.0 mmol) in THF (3 mL) was added at −78° C. The resulting solution was stirred for 1 h at −78° C. The reaction was then quenched with water (30 mL). The resulting mixture was extracted with ethyl acetate (3×30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:2 ethyl acetate/pet. ether) to give benzyl N-[(3R)-7-(4-hydroxythian-4-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]carbamate as a light yellow solid. MS: (ESI, m/z): 400 [M+H]⁺.

Step 2. Benzyl N-[(3R)-7-(4-cyanothian-4-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]carbamate

A solution of TMSCN (120 mg, 1.21 mmol) in DCM (1 mL) was added to a mixture of InBr₃ (11.0 mg, 0.030 mmol) and DCM (1 mL). Then a solution of benzyl N-[(3R)-7-(4-hydroxythian-4-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]carbamate (120 mg, 0.300 mmol) in DCM (1 mL) was added over 30 min. The resulting mixture was stirred for 30 min at 29° C. Three batches were thus run in parallel and combined for quenching with water (10 mL). The resulting mixture was extracted with DCM (3×15 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by a silica gel chromatography (eluting with 1:3 ethyl acetate/pet. ether) to give benzyl N-[(3R)-7-(4-cyanothian-4-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]carbamate as an off-white solid. MS: (ESI, m/z): 409 [M+H]⁺.

Step 3. Benzyl N-[(3R)-7-(4-cyano-1,1-dioxo-1λ6-thian-4-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]carbamate

A mixture of benzyl N-[(3R)-7-(4-cyanothian-4-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]carbamate (160 mg, 0.390 mmol) and oxone (650 mg, 3.87 mmol) in 2-butanone (10 mL) was stirred for 12 h at 40° C. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was purified via a silica gel chromatography (eluting with 1:1 ethyl acetate/pet. ether) to give benzyl N-[(3R)-7-(4-cyano-1,1-dioxo-1λ6-thian-4-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]carbamate as a white solid. MS: (ESI, m/z): 441 [M+H]⁺.

Step 4. 4-[(3R)-3-Amino-3,4-dihydro-2H-1-benzopyran-7-yl]-1,1-dioxo-1λ6-thiane-4-carbonitrile

A mixture of benzyl N-[(3R)-7-(4-cyano-1,1-dioxo-1λ6-thian-4-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]carbamate (80.0 mg, 0.180 mmol) and palladium on carbon (80.0 mg, 10%) in ethyl acetate (10 mL) was stirred for 1 h at 29° C. under hydrogen atmosphere (balloon). The solids were filtered out. The filtrate was concentrated under vacuum to afford 4-[(3R)-3-amino-3,4-dihydro-2H-1-benzopyran-7-yl]-1,1-dioxo-1λ6-thiane-4-carbonitrile as an off-white solid. MS: (ESI, m/z): 307 [M+H]⁺.

Step 5. 3-Amino-N-[(3R)-7-(4-cyano-1,1-dioxo-1λ6-thian-4-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide

HBTU (68.0 mg, 0.180 mmol) was added to a solution of 4-[(3R)-3-amino-3,4-dihydro-2H-1-benzopyran-7-yl]-1,1-dioxo-1λ6-thiane-4-carbonitrile (50.0 mg, 0.160 mmol), Et₃N (0.067 mL, 0.480 mmol) and 3-amino-6-methylthieno[2,3-b]pyridine-2-carboxylic acid (34.0 mg, 0.160 mmol) in DMA (2 mL). The resulting solution was stirred for 30 min at 29° C. The mixture was purified by prep-HPLC (Column: XBridge Prep C18 OBD, 19×150 mm 5 μm; Mobile phase, A: water (10 mM NH₄HCO₃) and B: ACN (30% to 60% in 7 min)). The collected fraction was lyophilized to give 3-amino-N-[(3R)-7-(4-cyano-1,1-dioxo-1λ6-thian-4-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide as a light yellow solid. MS (ESI, m/z): 497 [M+H]⁺. ¹H NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.33 (d, J=8.4 Hz, 1H), 7.63 (d, J=7.6 Hz, 1H), 7.32 (d, J=8.4 Hz, 2H), 7.24-7.22 (m, 3H), 7.10-7.08 (m, 1H), 6.99 (d, J=2.0 Hz, 1H), 4.37-4.32 (m, 1H), 4.26-4.22 (m, 1H), 3.93-3.88 (m, 1H), 3.42-3.27 (m, 4H), 3.01-2.99 (m, 2H), 2.59-2.50 (m, 7H).

Example 35. 3-Amino-6-methyl-N-[(3R)-5,6,8-trifluoro-7-(piperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]thieno[2,3-b]pyridine-2-carboxamide

Step 1. Benzyl 4-(2,3,5,6-tetrafluoro-4-formylphenyl)piperazine-1-carboxylate

A solution of 2,3,4,5,6-pentafluorobenzaldehyde (10.0 g, 51.0 mmol), benzyl piperazine-1-carboxylate (11.2 g, 50.8 mmol) and DIEA (15.9 mL, 95.9 mmol) in DMF (50 mL) was stirred for 12 h at 60° C. The reaction was quenched by the addition of water (50 mL), and extracted with ethyl acetate (3×50 mL). The organic layers were combined, washed with water (6×100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:5 ethyl acetate/pet. ether) to give benzyl 4-(2,3,5,6-tetrafluoro-4-formylphenyl)piperazine-1-carboxylate as a white solid. MS (ESI, m/z): 397 [M+H]⁺.

Step 2. Benzyl 4-[2,3,5,6-tetrafluoro-4-(hydroxymethyl)phenyl]piperazine-1-carboxylate

To a solution of benzyl 4-(2,3,5,6-tetrafluoro-4-formylphenyl)piperazine-1-carboxylate (4.00 g, 10.1 mmol) in methanol (40 mL) was added NaBH₄ (950 mg, 25.1 mmol) at <10° C. The resulting solution was stirred for 2 h at 25° C. The solvent was removed under vacuum. The residue was diluted with water (100 mL). The resulting mixture was extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give benzyl 4-[2,3,5,6-tetrafluoro-4-(hydroxymethyl)phenyl]piperazine-1-carboxylate as a white solid. MS: (ESI, m/z): 399 [M+H]⁺.

Step 3. Benzyl 4-[4-(bromomethyl)-2,3,5,6-tetrafluorophenyl]piperazine-1-carboxylate

A solution of benzyl 4-[2,3,5,6-tetrafluoro-4-(hydroxymethyl)phenyl]piperazine-1-carboxylate (5.70 g, 14.3 mmol) and PBr₃ (3.85 g, 14.2 mmol) in DCM (40 mL) was stirred for 2 h at 25° C. The reaction was then quenched by the addition of water (40 mL). The resulting mixture was extracted with DCM (3×30 mL). The organic layers were combined, washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give benzyl 4-[4-(bromomethyl)-2,3,5,6-tetrafluorophenyl]piperazine-1-carboxylate as a white solid. MS (ESI, m/z): 461, 463 [M+H]⁺.

Step 4. Benzyl 4-(4-[[(2R,5S)-3,6-dimethoxy-5-(propan-2-yl)-2,5-dihydropyrazin-2-yl]methyl]-2,3,5,6-tetrafluorophenyl)piperazine-1-carboxylate

To a solution of (25)-3,6-dimethoxy-2-(propan-2-yl)-2,5-dihydropyrazine (1.84 g, 9.99 mmol) in THF (50 mL) was added n-BuLi (6.0 mL, 2.5M in n-hexane) at −78° C. The resulting solution was stirred for 30 min at −78° C. To this was added benzyl 4-[4-(bromomethyl)-2,3,5,6-tetrafluorophenyl]piperazine-1-carboxylate (4.60 g, 9.97 mmol) at −78° C. The resulting solution was stirred for 2 h at −78° C. The reaction was then quenched by the addition of NH₄C₁ (sat., aq.) (40 mL). The resulting mixture was extracted with ethyl acetate (3×30 mL). The organic layers were combined, washed with brine (3×30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by reversed phase chromatography (Column: C₁₈ silica gel; Mobile phase, A: water (containing 0.05% TFA) and B: ACN (5% to 75% in 30 min) to give benzyl 4-(4-[[(2R,5S)-3,6-dimethoxy-5-(propan-2-yl)-2,5-dihydropyrazin-2-yl]methyl]-2,3,5,6-tetrafluorophenyl)piperazine-1-carboxylate as yellow oil. MS (ESI, m/z): 565 [M+H]⁺.

Step 5. Benzyl 4-[4-[(2R)-2-amino-3-methoxy-3-oxopropyl]-2,3,5,6-tetrafluorophenyl]piperazine-1-carboxylate

Hydrochloric acid (100 mL, 0.3N) was added into a stirring solution of benzyl 4-(4-[[(2R,5S)-3,6-dimethoxy-5-(propan-2-yl)-2,5-dihydropyrazin-2-yl]methyl]-2,3,5,6-tetrafluorophenyl)piperazine-1-carboxylate (5.86 g, 10.3 mmol) in ACN (100 mL) at <10° C. The resulting solution was stirred for 1 h at 25° C. The solvent was removed under vacuum. The pH value of the residue was adjusted to 9-10 with NaHCO₃ (sat. aq.). The resulting mixture was extracted with ethyl acetate (3×30 mL). The organic layers were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give benzyl 4-[4-[(2R)-2-amino-3-methoxy-3-oxopropyl]-2,3,5,6-tetrafluorophenyl]piperazine-1-carboxylate as a yellow solid. MS (ESI, m/z): 470 [M+H]⁺.

Step 6. Benzyl 4-[4-[(2R)-2-amino-3-hydroxypropyl]-2,3,5,6-tetrafluorophenyl]piperazine-1-carboxylate

Into a solution of benzyl 4-[4-[(2R)-2-amino-3-methoxy-3-oxopropyl]-2,3,5,6-tetrafluorophenyl]piperazine-1-carboxylate (3.83 g, 8.16 mmol) in methanol (10 mL) and THF (40 mL) was added NaBH₄ (900 mg, 23.7 mmol) at <10° C. The resulting solution was stirred for 3 h at 25° C. The solvent was concentrated under vacuum. The residue was diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (3×50 mL). The organic layers were combined, washed with brine (3×30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by reversed phase chromatography (Column: C₁₈ silica gel; Mobile phase, A: water (containing 0.05% TFA) and B: ACN (5% to 80% in 30 min)) to afford benzyl 4-[4-[(2R)-2-amino-3-hydroxypropyl]-2,3,5,6-tetrafluorophenyl]piperazine-1-carboxylate as a yellow oil. MS (ESI, m/z): 442 [M+H]⁺.

Step 7. Benzyl 4-[(3R)-3-amino-5,6,8-trifluoro-3,4-dihydro-2H-1-benzopyran-7-yl]piperazine-1-carboxylate

Sodium hydride (34.0 mg, 1.42 mmol, 60%) was added into a stirring solution of benzyl 4-[4-[(2R)-2-amino-3-hydroxypropyl]-2,3,5,6-tetrafluorophenyl]piperazine-1-carboxylate (400 mg, 0.910 mmol) in DMSO (10 mL). The resulting solution was stirred for 30 min at 25° C. and then 2 h at 70° C. After cooling to 25° C., the reaction was quenched by the addition of water (40 mL). The resulting mixture was extracted with ethyl acetate (3×20 mL). The organic layers were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by reversed phase chromatography (Column: C₁₈ silica gel; Mobile phase, A: water (containing 0.05% TFA) and B: ACN (20% to 70% in 30 min)) to give benzyl 4-[(3R)-3-amino-5,6,8-trifluoro-3,4-dihydro-2H-1-benzopyran-7-yl]piperazine-1-carboxylate as a yellow oil. MS (ESI, m/z): 422 [M+H]⁺.

Step 8. Benzyl 4-[(3R)-3-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,8-trifluoro-3,4-dihydro-2H-1-benzopyran-7-yl]piperazine-1-carboxylate

To a solution of benzyl 4-[(3R)-3-amino-5,6,8-trifluoro-3,4-dihydro-2H-1-benzopyran-7-yl]piperazine-1-carboxylate (70.0 mg, 0.170 mmol) and 3-amino-6-methylthieno[2,3-b]pyridine-2-carboxylic acid (41.5 mg, 0.200 mmol) in DMA (2 mL) was added Et₃N (0.068 mL, 0.49 mmol) and HBTU (75.0 mg, 0.200 mmol). The resulting solution was stirred for 1 h at 25° C. The mixture was purified by reversed phase chromatography (Column: C₁₈ silica gel; Mobile phase, A: water (containing 0.05% TFA) and B: ACN (5% to 80% in 30 min)) to afford benzyl 4-[(3R)-3-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,8-trifluoro-3,4-dihydro-2H-1-benzopyran-7-yl]piperazine-1-carboxylate as a yellow oil. MS (ESI, m/z): 612 [M+H]⁺.

Step 9. 3-Amino-6-methyl-N-[(3R)-5,6,8-trifluoro-7-(piperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]thieno[2,3-b]pyridine-2-carboxamide

To a solution of benzyl 4-[(3R)-3-[3-amino-6-methylthieno[2,3-b]pyridine-2-amido]-5,6,8-trifluoro-3,4-dihydro-2H-1-benzopyran-7-yl]piperazine-1-carboxylate (50.0 mg, 0.080 mmol) in CH₃COOH (1.5 mL) was added hydrobromic acid (1.5 mL, 48%). The resulting solution was stirred for 1 h at 50° C. The resulting mixture was concentrated under vacuum. The residue was purified by prep-HPLC (Column: XBridge Shield RP18 OBD Column; Mobile phase, A: water (containing 10 mmol/L NH₄HCO₃) and B: ACN (25% to 65% B in 8 min)). The collected fraction was lyophilized to give 3-amino-6-methyl-N-[(3R)-5,6,8-trifluoro-7-(piperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]thieno[2,3-b]pyridine-2-carboxamide as a white solid. MS (ESI, m/z): 478 [M+H]⁺. ¹H NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.33 (d, J=8.4 Hz, 1H), 7.70 (d, J=6.8 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.25 (br s, 2H), 4.36-4.30 (m, 1H), 4.26-4.23 (m, 1H), 3.99-3.95 (m, 1H), 3.04-2.94 (m, 5H), 2.90-2.84 (m, 1H), 2.79-2.77 (m, 4H), 2.58 (s, 3H).

Example A-1(a): Biochemical Assay: Ubiquitin-Rhodamine 110 Assay for USP28 Activity

The assay was performed in a final volume of 9 μL in assay buffer containing 20 mM Tris-HCl (pH 8.0, (1M Tris-HCl, pH 8.0 solution; Corning 46-031-CM)), 3 mM BME (2-Mercaptoethanol; Sigma 63689-25ML-F), 0.03% BGG (0.22 μM filtered, Sigma, G7516-25G), and 0.01% Triton X-100 (Sigma, T9284-10L). Nanoliter quantities of 10-point, 3-fold serial dilution in DMSO was pre-dispensed into 1536 assay plates (Corning, #3724BC) for a final test concentration of 25 μM to 1.3 nM, top to lowest dose, respectively. Enzyme USP28, construct His-tagged USP28-FL-mammalian, (protein expression and purification procedure described below). Concentration and incubation times were optimized for the maximal signal-to-background while maintaining initial velocity conditions at a fixed substrate concentration. The final concentration of the enzyme in the assay was 75 μM. Final substrate (Ub-Rh110; Ubiquitin-Rhodamine 110, UbiQ-126) concentration was 25 nM with [Ub-Rh110]<<Km. 3 μL of 2× enzyme was added to assay plates (pre-stamped with compound) preincubated with USP25 for 30 minutes and then 3 μL of 2×Ub-Rh110 was added to assay plates. Plates were incubated for 45 minutes at room temperature before addition of 3 μL of stop solution (final concentration of 10 mM citric acid (Sigma, 251275-500G)). Fluorescence was read on the Envision (Excitation at 485 nm and Emission at 535 nm; Perkin Elmer) or on the PheraSTAR (Excitation at 485 nm and Emission at 535 nm; BMG Labtech).

Procedure for the Protein Expression and Purification for Construct His-Tagged USP28-FL-Mammalian

Expression of USP28 (1-1077)-TEV-6*His (pTT5 vector) was carried out in Expi293f cells (sequence derived from uniprot ID: Q96RU2-1). Cells were re-suspended in lysis buffer B 50 mM Bicine, pH 8.0, 20 mM NaCl, 5% glycerol, 0.1% CHAPS, 5 mM β-ME, 1 mM PMSF, 1 ug/ml Leupeptin, 1 ug/ml Pepstatin) and lysed by sonication. Insoluble material was removed by centrifugation and the supernatant was loaded onto a Ni-NTA column (GE Healthcare) equilibrated with Ni Buffer A (50 mM Bicine, pH 8.0, 20 mM NaCl, 5% glycerol, 0.1% CHAPS, 5 mM β-ME.) and washed with Ni Buffer A+20 mM imidazole until A₂₈₀ reached baseline. The protein was eluted with Ni Buffer B (50 mM Bicine, pH 8.0, 20 mM NaCl, 5% glycerol, 0.1% CHAPS, 5 mM β-ME, 300 mM imidazole.). The protein was further purified using a Superdex™ 200 10/300 GL column (GE Healthcare) equilibrated with 50 mM Bicine, pH 8.0, 20 mM NaCl, 5% glycerol, 0.1% CHAPS, 5 mM β-ME. The protein was concentrated to 2.5 mg ml⁻¹, flash-frozen in liquid N₂ and stored at −80° C.

Example A-1(b): Biochemical Assay: Ubiquitin-Rhodamine 110 Assay for USP28 Activity

Each assay was performed in a final volume of 20 μL in assay buffer containing 20 mM Tris-HCl (pH 8.0, (1M Tris-HCl, pH 8.0 solution; Corning 46-031-CM)), 2 mM CaCl₂) (1M Calcium Chloride solution; Sigma #21114) 2 mM BME (2-Mercaptoethanol; Sigma 63689-25ML-F), 0.01% Prionex (0.22 μM filtered, Sigma #G-0411), and 0.01% Triton X-100. Stock compound solutions were stored at −20° C. as 10 mM in DMSO. Up to 1 month prior to the assay, 2 mM test compounds were pre-dispensed into assay plates (Black, low volume; Corning #3820) and frozen at −20° C. Prestamped assay plates were allowed to come to room temperature on the day of the assay. For the screen, 100 nL of 2 mM was pre-dispensed for a final screening concentration of 10 μM (DMSO_((fc))=0.5%). Enzyme (USP28, construct USP28 (USP28-5(1-1077)-TEV-6*His; LifeSensors) concentration and incubation times were optimized for the maximal signal-to-background while maintaining initial velocity conditions at a fixed substrate concentration. The final concentration of the enzyme in the assay was 400 pM. Final substrate (Ub-Rh110; Ubiquitin-Rhodamine 110, R&D Systems #U-555) concentration was 25 nM with [Ub-Rh110]<<Km. 10 of 2× enzyme was added to assay plates (pre-stamped with compound) either simultaneously with 2×Ub-Rh110 or preincubated with USP28 40 minutes prior to the addition of 10 μL of 2×Ub-Rh110 to compound plates. Plates were incubated stacked for 90 minutes at room temperature before fluorescence was read on the Envision (Excitation at 485 nm and Emission at 535 nm; Perkin Elmer) or on the PheraSTAR (Excitation at 485 nm and Emission at 535 nm; BMG Labtech).

For follow-up studies, each assay was performed in a final volume of 15 μL in assay buffer containing 20 mM Tris-HCl (pH 8.0, (1M Tris-HCl, pH 8.0 solution; Corning 46-031-CM)), 3 mM BME (2-Mercaptoethanol; Sigma 63689-25ML-F), 0.03% BGG (0.22 μM filtered, Sigma, G7516-25G), and 0.01% Triton X-100 (Sigma, T9284-10L). Nanoliter quantities of either an 8-point or 10-point, 3-fold serial dilution in DMSO was pre-dispensed into assay plates (Perkin Elmer, ProxiPlate-384 F Plus, #) for a final test concentration of either 25 μM to 11 nM or 25 μM to 1.3 nM, respectively. Enzyme USP28, construct USP28 (USP28-5(1-1077)-TEV-6*His; LifeSensors) concentration and incubation times were optimized for the maximal signal-to-background while maintaining initial velocity conditions at a fixed substrate concentration. The final concentration of the enzyme in the assay was 75 pM. Final substrate (Ub-Rh110; Ubiquitin-Rhodamine 110, R&D Systems #U-555) concentration was 25 nM with [Ub-Rh110]<<Km. 5 μL of 2× enzyme was added to assay plates (pre-stamped with compound) preincubated with USP28 for 30 minutes and then 5 μL of 2×Ub-Rh110 was added to assay plates. Plates were incubated stacked for 20 minutes at room temperature before 5 μL of stop solution was added (final concentration of 10 mM citric acid (Sigma, 251275-500G)). Fluorescence was read on the Envision (Excitation at 485 nm and Emission at 535 nm; Perkin Elmer) or on the PheraSTAR (Excitation at 485 nm and Emission at 535 nm; BMG Labtech).

Example A-2: Biochemical Assay: Ubiquitin-Rhodamine 110 Assay for USP25 Activity

The assay was performed in a final volume of 9 μL in assay buffer containing 20 mM Tris-HCl (pH 8.0, (1M Tris-HCl, pH 8.0 solution; Corning 46-031-CM)), 3 mM BME (2-Mercaptoethanol; Sigma 63689-25ML-F), 0.03% BGG (0.22 μM filtered, Sigma, G7516-25G), and 0.01% Triton X-100 (Sigma, T9284-10L). Nanoliter quantities of 10-point, 3-fold serial dilution in DMSO was pre-dispensed into 1536 assay plates (Corning, #3724BC) for a final test concentration of 25 μM to 1.3 nM, top to lowest dose, respectively. Enzyme USP25, construct USP25-His6, (Boston Biochem E-546). Concentration and incubation times were optimized for the maximal signal-to-background while maintaining initial velocity conditions at a fixed substrate concentration. The final concentration of the enzyme in the assay was 75 pM. Final substrate (Ub-Rh110; Ubiquitin-Rhodamine 110, R&D Systems #U-555) concentration was 25 nM with [Ub-Rh110]<<Km. 3 μL of 2× enzyme was added to assay plates (pre-stamped with compound) preincubated with USP25 for 30 minutes and then 3 μL of 2×Ub-Rh110 was added to assay plates. Plates were incubated for 45 minutes at room temperature before addition of 3 μL of stop solution (final concentration of 10 mM citric acid (Sigma, 251275-500G)). Fluorescence was read on the Envision (Excitation at 485 nm and Emission at 535 nm; Perkin Elmer) or on the PheraSTAR (Excitation at 485 nm and Emission at 535 nm; BMG Labtech).

For assay formats Example A-1(a), A-1(b), and A-2, data were reported as percent inhibition compared with control wells based on the following equation: % inh=1−((FLU−Ave_(Low))/(Ave_(High)−Ave_(Low))) where FLU=measured Fluorescence, Ave_(Low)=average Fluorescence of no enzyme control (n=16), and Ave_(High)=average Fluorescence of DMSO control (n=16). IC₅₀ values were determined by curve fitting of the standard 4 parameter logistic fitting algorithm included in the Activity Base software package: IDBS XE Designer Model 205. Data is fitted using the Levenburg Marquardt algorithm.

The activity of compounds in the biochemical IC₅₀ assays (IC₅₀ ranges) according to the present disclosure are reported in Table 24 below according to the following:

-   “+”: >2 μM; “++”: 0.2-2 μM; “+++”: 0.05-0.2 μM; “++++”: 0.001-0.05     μM.

TABLE 24 MS m/z USP28 USP28 USP25 Ex. # Chemical Name [M + H]+ 1H NMR A-1(a) A-1(b) A-2 1-1 (R)-3-amino-6-methyl-N-(7- see see above ++++ +++ ++ (piperazin-1-yl)chroman-3- above yl)thieno[2,3-b]pyridine-2- carboxamide 1-2 (S)-3-amino-6-methyl-N-(7- see see above ++ + + (piperazin-1-yl)chroman-3- above yl)thieno[2,3-b]pyridine-2- carboxamide 1-3 N-((3R)-7-(3,8- see diazabicyclo[3.2.1]octan-3- above see above ++++ +++ ++++ yl)chroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2- carboxamide 1-4 N-((3S)-7-(3,8- see see above ++ ++ + diazabicyclo[3.2.1]octan-3- above yl)chroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2- carboxamide 1-5 N-((3R)-7-(3,9- see see above ++++ ++++ ++++ diazabicyclo[3.3.1]nonan-3- above yl)chroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2- carboxamide 1-6 N-((3S)-7-(3,9- see see above +++ ++ + diazabicyclo[3.3.1]nonan-3- above yl)chroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2- carboxamide 1-7 3-amino-N-((R)-7-((2R,3S)-2,3- see see above ++++ ++++ dimethylpiperazin-1-yl)chroman- above 3-yl)-6-methylthieno[2,3- b]pyridine-2-carboxamide 1-8 3-amino-N-((S)-7-((2R,3S)-2,3- see see above ++++ dimethylpiperazin-1-yl)chroman- above 3-yl)-6-methylthieno[2,3- b]pyridine-2-carboxamide 1-9 3-amino-N-((R)-7-((2S,3R)-2,3- see see above ++++ ++ ++ dimethylpiperazin-1-yl)chroman- above 3-yl)-6-methylthieno[2,3- b]pyridine-2-carboxamide 1-10 3-amino-N-((S)-7-((2S,3R)-2,3- see see above ++++ ++ ++ dimethylpiperazin-1-yl)chroman- above 3-yl)-6-methylthieno[2,3- b]pyridine-2-carboxamide 1-11 3-amino-N-((R)-7-((2R,3R)-2,3- see see above ++++ ++++ +++ dimethylpiperazin-1-yl)chroman- above 3-yl)-6-methylthieno[2,3- b]pyridine-2-carboxamide 1-12 3-amino-N-((S)-7-((2R,3R)-2,3- see see above ++++ ++++ ++++ dimethylpiperazi1-1-yl)chroman- above 3-yl)-6-methylthieno[2,3- b]pyridine-2-carboxamide 1-13 3-amino-N-((R)-7-((2S,3S)-2,3- dimethylpiperazin-1-yl)chroman- see see above +++ ++ ++ 3-yl)-6-methylthieno[2,3- above b]pyridine-2-carboxamide 1-14 3-amino-N-((S)-7-((2S,3S)-2,3- see see above +++ ++ ++ dimethylpiperazin-1-yl)chroman- above 3-yl)-6-methylthieno[2,3- b]pyridine-2-carboxamide 1-15 (R)-3-amino-5-fluoro-6-methyl- see see above ++++ +++ +++ N-(7-(piperazin-1-yl)chroman-3- above yl)thieno[2,3-b]pyridine-2- carboxamide 1-16 (S)-3-amino-5-fluoro-6-methyl- see see above ++ + + N-(7-(piperazin-1-yl)chroman-3- above yl)thieno[2,3-b]pyridine-2- carboxamide 1-17 N-((3R)-7-(3,8- see see above +++ ++ ++ diazabicyclo[3.2.1]octan-3- above yl)chroman-3-yl)-3-amino-5- fluorothieno[2,3-b]pyridine-2- carboxamide 1-18 N-((3S)-7-(3,8- see see above + + + diazabicyclo[3.2.1]octan-3- above yl)chroman-3-yl)-3-amino-5- fluorothieno[2,3-b]pyridine-2- carboxamide 1-19 N-((3R)-7-(3,8- see see above ++++ ++++ +++ diazabicyclo[3.2.1]octan-3- above yl)chroman-3-yl)-7-amino-3- methylthieno[2,3-b]pyrazine-6- carboxamide 1-20 N-((3S)-7-(3,8- see see above ++ ++ + diazabicyclo[3.2.1]octan-3- above yl)chroman-3-yl)-7-amino-3- methylthieno[2,3-b]pyrazine-6- carboxamide 1-21 (R)-7-amino-3-methyl-N-(7- see see above ++++ ++ ++ (piperazin-1-yl)chroman-3- above yl)thieno[2,3-b]pyrazine-6- carboxamide 1-22 (S)-7-amino-3-methyl-N-(7- (piperazin-1-yl)chroman-3- see see above ++ + + yl)thieno[2,3-b]pyrazine-6- above carboxamide 1-23 N-((3R)-7-(3,8- see see above ++++ ++ ++ diazabicyclo[3.2.1]octan-3- above yl)chroman-3-yl)-6-amino-2- methylthieno[2,3-d]thiazole-5- carboxamide 1-24 N-((3S)-7-(3,8- see see above ++ + + diazabicyclo[3.2.1]octan-3- above yl)chroman-3-yl)-6-amino-2- methylthieno[2,3-d]thiazole-5- carboxamide 1-25 (R)-6-amino-2-methyl-N-(7- see see above ++++ ++ ++ (piperazin-1-yl)chroman-3- above yl)thieno[2,3-d]thiazole-5- carboxamide 1-26 (S)-6-amino-2-methyl-N-(7- see see above ++ + + (piperazin-1-yl)chroman-3- above yl)thieno[2,3-d]thiazole-5- carboxamide 1-27 N-((3S)-7-(3,8- see see above ++ + + diazabicyclo[3.2.1]octan-3- above yl)chroman-3-yl)-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5- carboxamide 1-28 N-((3R)-7-(3,8- see see above ++++ +++ +++ diazabicyclo[3.2.1]octan-3- above yl)chroman-3-yl)-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5- carboxamide 1-29 N-((3R)-7-(3,8- see see above +++ diazabicyclo[3.2.1]octan-3-yl)-5- above fluorochroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2- carboxamide 1-30 N-((3S)-7-(3,8- see see above ++ + + diazabicyclo[3.2.1]octan-3-yl)-5- above fluorochroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2- carboxamide 1-31 (R)-3-amino-6-methyl-N-(7- see see above ++ + + (piperazin-1-yl)-6- above (trifluoromethoxy)chroman-3- yl)thieno[2,3-b]pyridine-2- carboxamide 1-32 (S)-3-amino-6-methyl-N-(7- (piperazin-1-yl)-6- (trifluoromethoxy)chroman-3- see see above +++ ++ ++ ylthieno[2,3-b]pyridine-2- above carboxamide 1-33 (R)-3-amino-N-(8-fluoro-7- see see above ++++ +++ +++ (piperazin-1-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2- above carboxamide 1-34 (S)-3-amino-N-(8-fluoro-7- see see above ++ + + (piperazin-1-yl)chroman-3-yl)-6- above methylthieno[2,3-b]pyridine-2- carboxamide 1-35 (R)-3-amino-N-(6-fluoro-7- see see above ++++ +++ ++ (piperazin-1-yl)chroman-3-yl)-6- above methylthieno[2,3-b]pyridine-2- carboxamide 1-36 (S)-3-amino-N-(6-fluoro-7- see see above + + + (piperazin-1-yl)chroman-3-yl)-6- above methylthieno[2,3-b]pyridine-2- carboxamide 1-37 (R)-6-amino-N-(5-fluoro-7- see see above + + + (piperazin-1-yl)chroman-3-yl)-2- above methylthieno[2,3-d]thiazole-5- carboxamide 1-38 (S)-6-amino-N-(5-fluoro-7- see see above ++++ ++ ++ (piperazin-1-yl)chroman-3-yl)-2- above methylthieno[2,3-d]thiazole-5- carboxamide 1-39 N-((3R)-7-(3,8- see see above ++++ ++ ++ diazabicyclo[3.2.1]octan-3-yl)-5- above fluorochroman-3-yl)-6-amino-2- methylthieno[2,3-d]thiazole-5- carboxamide 1-40 N-((3S)-7-(3,8- see see above ++ + + diazabicyclo[3.2.1]octan-3-yl)-5- above fluorochroman-3-yl)-6-amino-2- methylthieno[2,3-d]thiazole-5- carboxamide 1-41 N-((3S)-7-(3,6- see see above ++++ +++ +++ diazabicyclo[3.1.1]heptan-3-yl)- above 5-fluorochroman-3-yl)-3-amino- 6-methylthieno[2,3-b]pyridine-2- carboxamide 1-42 N-((3R)-7-(3,6- see see above ++ + + diazabicyclo[3.1.1]heptan-3-yl)- above 5-fluorochroman-3-yl)-3-amino- 6-methylthieno[2,3-b]pyridine-2- carboxamide 2-1 3-amino-N-((3R)-7-(9,9-difluoro- see see above ++++ ++++ ++++ 3,7-diazabicyclo[3.3.1]nonan-3- above yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 2-2 N-((3R)-7-(3,6- see see above ++++ +++ +++ diazabicyclo[3.1.1]heptan-3- above yl)chroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2- carboxamide 2-3 N-((3S)-7-(3,6- see see above ++ + + diazabicyclo[3.1.1]heptan-3- above yl)chroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2- carboxamide 2-4 3-amino-6-methyl-N-((R)-7-((S)- see see above ++++ ++++ ++++ 2-methylpiperazin-1- above yl)chroman-3-yl)thieno[2,3- b]pyridine-2-carboxamide 2-5 3-amino-6-methyl-N-((R)-7-((R)- see see above ++++ ++++ ++++ 2-methylpiperazin-1- above yl)chroman-3-yl)thieno[2,3- b]pyridine-2-carboxamide 2-6 N-((3R)-7-(3,8- see see above ++++ +++ +++ diazabicyclo[3.2.1]octan-8- above yl)chroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2- carboxamide 2-7 (R)-N-(7-(2,5- see see above ++++ +++ ++ diazaspiro[3.4]octan-5- above yl)chroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2- carboxamide 2-8 3-amino-6-methyl-N-((R)-7-((S)- see see above ++++ ++ ++ 3-methylpiperazin-1- above yl)chroman-3-yl)thieno[2,3- b]pyridine-2-carboxamide 2-9 3-amino-6-methyl-N-((R)-7-((R)- see see above ++++ ++ ++ 3-methylpiperazin-1- above yl)chroman-3-yl)thieno[2,3- b]pyridine-2-carboxamide 2-10 (R)-N-(7-(2-oxa-5,8- see see above ++++ +++ +++ diazaspiro[3.5]nonan-5- above yl)chroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2- carboxamide 2-11 N-((3R)-7-(3,6- see see above ++++ ++ +++ diazabicyclo[3.1.1]heptan-3- above yl)chroman-3-yl)-7-amino-3- methylthieno[2,3-b]pyrazine-6- carboxamide 2-12 N-((3R)-7-(3-oxa-7,9- see see above +++ ++ ++ diazabicyclo[3.3.1]nonan-7- above yl)chroman-3-yl)-7-amino-3- methylthieno[2,3-b]pyrazine-6- carboxamide 2-13 N-((3R)-7-(9-oxa-3,7- see see above ++++ ++ ++ diazabicyclo[3.3.1]nonan-3- above yl)chroman-3-yl)-7-amino-3- methylthieno[2,3-b]pyrazine-6- carboxamide 2-14 N-((3R)-7-(3,6- see see above ++++ ++ diazabicyclo[3.1.1]heptan-3- above yl)chroman-3-yl)-3-amino-6- fluorothieno[2,3-b]pyridine-2- carboxamide 2-15 N-((3R)-7-(3,6- see see above ++++ +++ diazabicyclo[3.1.1]heptan-3- yl)chroman-3-yl)-3-amino-5- fluoro-6-methylthieno[2,3- above b]pyridine-2-carboxamide 2-16 (R)-3-amino-5-fluoro-6- see see above +++ ++ ++ methoxy-N-(7-(piperazin-1- above yl)chroman-3-yl)thieno[2,3- b]pyridine-2-carboxamide 2-17 (R)-3-amino-4,6-dimethyl-N-(7- see see above ++++ +++ +++ (piperazin-1-yl)chroman-3- above yl)thieno[2,3-b]pyridine-2- carboxamide 2-18 N-((3R)-7-(3,6- see see above ++++ +++ +++ diazabicyclo[3.1.1]heptan-3- above yl)chroman-3-yl)-3-amino-4,6- dimethylthieno[2,3-b]pyridine-2- carboxamide 2-19 3-amino-N-((3R)-7-(9,9-difluoro- see see above ++++ ++++ ++++ 3,7-diazabicyclo[3.3.1]nonan-3- above yl)chroman-3-yl)-4,6- dimethylthieno[2,3-b]pyridine-2- carboxamide 2-20 N-((3R)-7-(9-oxa-3,7- see see above ++++ +++ ++++ diazabicyclo[3.3.1]nonan-3- above yl)chroman-3-yl)-3-amino-4,6- dimethylthieno[2,3-b]pyridine-2- carboxamide 2-21 N-((3R)-7-(3,6- see see above ++++ ++ +++ diazabicyclo[3.1.1]heptan-3- above yl)chroman-3-yl)-3-amino-6- methyl-4- (trifluoromethyl)thieno[2,3- b]pyridine-2-carboxamide 2-22 3-amino-N-((3R)-7-(9,9-difluoro- see see above ++++ ++++ ++++ 3,7-diazabicyclo[3.3.1]nonan-3- above yl)chroman-3-yl)-6-methyl-4- (trifluoromethyl)thieno[2,3- b]pyridine-2-carboxamide 2-23 N-((3R)-7-(9-oxa-3,7- see see above ++++ ++++ diazabicyclo[3.3.1]nonan-3- above yl)chroman-3-yl)-3-amino-6- methyl-4- (trifluoromethyl)thieno[2,3- b]pyridine-2-carboxamide 2-24 N-((3R)-7-(3,8- see see above +++ + ++ diazabicyclo[3.2.1]octan-3- above yl)chroman-3-yl)-2′,3′-dihydro- 1′H-spiro[cyclopropane-1,4′- [1,8]naphthyridine]-6′- carboxamide 2-25 N-((3R)-7-(3,8- see see above +++ ++ +++ diazabicyclo[3.2.1]octan-3- above yl)chroman-3-yl)-6- (benzylamino)nicotinamide 2-26 N-((3R)-7-(3,6- see see above +++ ++ ++ diazabicyclo[3.1.1]heptan-3- above yl)chroman-3-yl)-6-amino-2- methylthieno[2,3-d]thiazole-5- carboxamide 2-27 N-((3R)-7-(3,9- see see above ++++ ++ ++ diazabicyclo[3.3.1]nonan-3- above yl)chroman-3-yl)-6-amino-2- methylthieno[2,3-d]thiazole-5- carboxamide 2-28 6-amino-N-((3R)-7-(9,9-difluoro- see see above ++++ +++ +++ 3,7-diazabicyclo[3.3.1]nonan-3- above yl)chroman-3-yl)-2- methylthieno[2,3-d]thiazole-5- carboxamide 2-29 N-((3R)-7-(3,9- see see above +++ ++ ++ diazabicyclo[3.3.1]nonan-3- above yl)chroman-3-yl)-7-ethyl-7H- pyrrolo[2,3-c]pyridazine-3- carboxamide 2-30 N-((3R)-7-(9,9-difluoro-3,7- see see above ++++ ++++ ++++ diazabicyclo[3.3.1]nonan-3- above yl)chroman-3-yl)-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5- carboxamide 2-31 (R)-3-amino-N-(8-cyano-5- see see above ++++ ++ fluoro-7-(piperazin-1- above yl)chroman-3-yl)-4,6- dimethylthieno[2,3-b]pyridine-2- carboxamide 2-32 (R)-3-amino-N-(6-cyano-5- see see above ++++ ++++ fluoro-7-(piperazin-1- above yl)chroman-3-yl)-4,6- dimethylthieno[2,3-b]pyridine-2- carboxamide 2-33 3-amino-N-((3R)-6-cyano-7- see see above ++++ ++++ ++++ (9,9-difluoro-3,7- above diazabicyclo[3.3.1]nonan-3- yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 2-34 (S)-7-amino-3-methyl-N-(7- see see above +++ ++ + methyl-6-(piperazin-1-yl)- above 1,2,3,4-tetrahydronaphthalen-2- yl)thieno[2,3-b]pyrazine-6- carboxamide 2-35 (R)-7-amino-3-methyl-N-(7- see see above + + + methyl-6-(piperazin-1-yl)- above 1,2,3,4-tetrahydronaphthalen-2- yl)thieno[2,3-b]pyrazine-6- carboxamide 2-36 (S)-7-amino-3-methyl-N-(5- see see above ++ + + methyl-6-(piperazin-1-yl)- above 1,2,3,4-tetrahydronaphthalen-2- yl)thieno[2,3-b]pyrazine-6- carboxamide 2-37 (R)-7-amino-3-methyl-N-(5- see see above ++++ +++ ++ methyl-6-(piperazin-1-yl)- above 1,2,3,4-tetrahydronaphthalen-2- yl)thieno[2,3-b]pyrazine-6- carboxamide 2-38 3-amino-N-[(3R)-7-[(3S,4S)-3- see see above +++ ++ amino-4- above (Â²Hâ,f)methoxypyrrolidin-1-yl]- 3,4-dihydro-2H-1-benzopyran-3- yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide 3-1 3-amino-N-((R)-7-((3S,4S)-3- see see above ++++ ++ amino-4-methoxypyrrolidin-1- above yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 3-2 3-amino-N-((R)-7-((3R,4R)-3- see see above ++++ ++ amino-4-methoxypyrrolidin-1- above yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 3-3 3-amino-N-((R)-7-((S)-3-amino- see see above ++++ ++++ +++ 3-(trifluoromethyl)piperidin-1- above yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 3-4 3-amino-N-((R)-7-((R)-3-amino- see see above ++++ +++ ++ 3-(trifluoromethyl)piperidin-1- above yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 3-5 3-amino-N-((R)-7-((3R,4S)-3- see see above ++++ +++ ++ amino-4-fluoropyrrolidin-1- above yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 3-6 3-amino-N-((R)-7-((3S,4R)-3- see see above ++++ ++ ++ amino-4-fluoropyrrolidin-1- above yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 3-7 3-amino-N-((R)-7-((3S,4S)-3- see see above ++++ ++ ++ amino-4-fluoropyrrolidin-1- above yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 3-8 3-amino-N-((R)-7-((3R,4R)-3- see see above ++++ ++ ++ amino-4-fluoropyrrolidin-1- above yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 3-9 3-amino-N-((R)-7-((3R,4R)-3- see see above +++ ++ amino-4- above (trifluoromethoxy)pyrrolidin-1- yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 3-10 3-amino-N-((R)-7-((3S,4S)-3- see see above +++ ++ amino-4- above (trifluoromethoxy)pyrrolidin-1- yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 3-11 3-amino-6-methyl-N-((R)-7-((R)- see see above +++ ++ ++ 3-(trifluoromethyl)piperazin-1- above yl)chroman-3-yl)thieno[2,3- b]pyridine-2-carboxamide 3-12 3-amino-6-methyl-N-((R)-7-((S)- see see above +++ ++ ++ 3-(trifluoromethyl)piperazin-1- above yl)chroman-3-yl)thieno[2,3- b]pyridine-2-carboxamide 3-13 N-((R)-7-((S)-2,7- see see above ++++ +++ ++ diazaspiro[4.5]decan-2- above yl)chroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2- carboxamide 3-14 N-((R)-7-((R)-2,7- see see above ++++ +++ +++ diazaspiro[4.5]decan-2- above yl)chroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2- carboxamide 3-15 (1aS,7bR)-N-((3R)-7-(3,8- see see above ++++ +++ diazabicyclo[3.2.1]octan-3- above yl)chroman-3-yl)-1a,2,3,7b- tetrahydro-1H- cyclopropa[c][1,8]naphthyridine- 6-carboxamide 3-16 (1aR,7bS)-N-((3R)-7-(3,8- see see above ++ + diazabicyclo[3.2.1]octan-3- above yl)chroman-3-yl)-1a,2,3,7b- tetrahydro-1H- cyclopropa[c][1,8]naphthyridine- 6-carboxamide 3-17 3-amino-N-[(3R)-6,8-difluoro-7- see see above ++++ +++ (piperazin-1-yl)-3,4-dihydro-2H- above 1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2- carboxamide 3-18 3-amino-N-[(3S)-6,8-difluoro-7- see see above ++ + (piperazin-1-yl)-3,4-dihydro-2H- above 1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2- carboxamide 4-1 (R)-N-(7-(2-oxa-5,8- see see above ++ diazaspiro[3.5]nonan-8- above yl)chroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2- carboxamide 5-1 (R)-3-amino-N-(7-(4,4- see see above ++++ ++++ +++ difluoropiperidin-1-yl)chroman- 3-yl)-6-methylthieno[2,3- above b]pyridine-2-carboxamide 5-2 (R)-3-amino-N-(7-(1,1- see see above ++++ +++ +++ dioxidothiomorpholino)chroman- above 3-yl)-6-methylthieno[2,3- b]pyridine-2-carboxamide 5-3 (R)-3-amino-N-(7-(3-hydroxy-3- see see above ++++ +++ ++ (trifluoromethyl)azetidin-1- above yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 5-4 3-amino-N-((3R)-7-(9,9-difluoro- see see above ++++ +++ +++ 3-oxa-7-azabicyclo[3.3.1]nonan- above 7-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 6-1 (R)-1-(3-(3-amino-6- see see above ++ ++ + methylthieno[2,3-b]pyridine-2- above carboxamido)chroman-7- yl)piperidine-4-carboxylic acid 6-2 (R)-1-((R)-3-(3-amino-6- see see above +++ ++ + methylthieno[2,3-b]pyridine-2- above carboxamido)chroman-7- yl)pyrrolidine-3-carboxylic acid 6-3 (S)-1-((R)-3-(3-amino-6- see see above +++ ++ + methylthieno[2,3-b]pyridine-2- above carboxamido)chroman-7- yl)pyrrolidine-3-carboxylic acid 6-4 (S)-1-(6-(7-amino-3- see see above ++ + + methylthieno[2,3-b]pyrazine-6- above carboxamido)-5,6,7,8- tetrahydronaphthalen-2- yl)azetidine-3-carboxylic acid 7-1 (R)-3-amino-N-(7-(4- see see above ++++ +++ ++ hydroxypiperidin-1-yl)chroman- above 3-yl)-6-methylthieno[2,3- b]pyridine-2-carboxamide 7-2 3-amino-N-((R)-7-((S)-3- see see above ++++ ++ hydroxy-3-methylpiperidin-1- above yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 7-3 3-amino-N-((R)-7-((R)-3- see see above ++++ ++ hydroxy-3-methylpiperidin-1- above yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 7-4 7-amino-N-((S)-6-((R)-6- see see above +++ ++ ++ hydroxy-1,4-diazepan-1-yl)- above 1,2,3,4-tetrahydronaphthalen-2- yl)-3-methylthieno[2,3- b]pyrazine-6-carboxamide 7-5 7-amino-N-((R)-6-((R)-6- see see above +++ ++ ++ hydroxy-1,4-diazepan-1-yl)- above 1,2,3,4-tetrahydronaphthalen-2- yl)-3-methylthieno[2,3- b]pyrazine-6-carboxamide 7-6 7-amino-N-((S)-6-((S)-6- see see above ++ ++ + hydroxy-1,4-diazepan-1-yl)- above 1,2,3,4-tetrahydronaphthalen-2- yl)-3-methylthieno[2,3- b]pyrazine-6-carboxamide 7-7 7-amino-N-((R)-6-((S)-6- see see above ++ + + hydroxy-1,4-diazepan-1-yl)- above 1,2,3,4-tetrahydronaphthalen-2- yl)-3-methylthieno[2,3- b]pyrazine-6-carboxamide 7-8 3-amino-N-((S)-6-((S)-3- see see above ++ + + (hydroxymethyl)piperazin-1-yl)- above 1,2,3,4-tetrahydronaphthalen-2- yl)-6-methylthieno[2,3- b]pyridine-2-carboxamide 7-9 3-amino-N-((S)-6-((R)-3- see see above ++ + + (hydroxymethyl)piperazin-1-yl)- above 1,2,3,4-tetrahydronaphthalen-2- yl)-6-methylthieno[2,3- b]pyridine-2-carboxamide 7-10 3-amino-N-((R)-6-((S)-3- see see above +++ ++ ++ (hydroxymethyl)piperazin-1-yl)- above 1,2,3,4-tetrahydronaphthalen-2- yl)-6-methylthieno[2,3- b]pyridine-2-carboxamide 7-11 3-amino-N-((R)-6-((R)-3- see see above +++ ++ ++ (hydroxymethyl)piperazin-1-yl)- above 1,2,3,4-tetrahydronaphthalen-2- yl)-6-methylthieno[2,3- b]pyridine-2-carboxamide 8-1 (R)-3-amino-N-(7-(4- see see above ++++ ++++ +++ fluoropiperidin-4-yl)chroman-3- above yl)-6-methylthieno[2,3- b]pyridine-2-carboxamide 9-1 N-((R)-7-(((S)-5-oxa-2- see see above ++++ +++ +++ azaspiro[3.4]octan-7- above yl)oxy)chroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2- carboxamide 9-2 N-((R)-7-(((R)-5-oxa-2- see see above ++++ +++ +++ azaspiro[3.4]octan-7- above yl)oxy)chroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2- carboxamide 10-1 (R)-3-amino-N-(5-fluoro-7- see see above ++++ +++ +++ (piperazin-1-yl)chroman-3-yl)-6- above methylthieno[2,3-b]pyridine-2- carboxamide 10-2 3-amino-N-((R)-7-((3R,4R)-3- see see above ++++ ++ amino-4-methoxypyrrolidin-1- above yl)-5-fluorochroman-3-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 10-3 3-amino-N-((R)-7-((3S,4S)-3- see see above ++++ ++ amino-4-methoxypyrrolidin-1- above yl)-5-fluorochroman-3-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 10-4 (R)-3-amino-N-(5-fluoro-7- see see above ++++ +++ (piperazin-1-yl-2,2,3,3,5,5,6,6- above d8)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 10-5 (S)-3-amino-N-(5-fluoro-7- see see above ++ + + (piperazin-1-yl)chroman-3-yl)-6- above methylthieno[2,3-b]pyridine-2- carboxamide 10-6 N-((3R)-7-(9-oxa-3,7- see see above ++++ ++++ +++ diazabicyclo[3.3.1]nonan-3-yl)- above 5-fluorochroman-3-yl)-3-amino- 6-methylthieno[2,3-b]pyridine-2- carboxamide 10-7 N-((3R)-7-(3,6- see see above ++++ +++ +++ diazabicyclo[3.1.1]heptan-3-yl)- above 5-fluorochroman-3-yl)-3-amino- 4,6-dimethylthieno[2,3- b]pyridine-2-carboxamide 10-8 N-((3R)-7-(3,6- see see above ++++ +++ +++ diazabicyclo[3.1.1]heptan-3-yl)- above 5-fluorochroman-3-yl)-7-amino- 3-methylthieno[2,3-b]pyrazine- 6-carboxamide 10-9 (R)-3-amino-N-(5-fluoro-7- see see above ++++ +++ +++ (piperazin-1-yl)chroman-3-yl)- above 4,6-dimethylthieno[2,3- b]pyridine-2-carboxamide 10-10 (R)-7-amino-N-(5-fluoro-7- see see above ++++ +++ +++ (piperazin-1-yl)chroman-3-yl)-3- above methylthieno[2,3-b]pyrazine-6- carboxamide 10-11 (R)-3-amino-N-(5-fluoro-7- see see above ++++ ++ +++ (piperazin-1-yl)chroman-3-yl)-6- above methoxythieno[2,3-b]pyridine-2- carboxamide 10-12 N-((3R)-7-(9-oxa-3,7- see see above ++++ ++++ ++++ diazabicyclo[3.3.1]nonan-3-yl)- above 5-fluorochroman-3-yl)-7-amino- 3-methylthieno[2,3-b]pyrazine- 6-carboxamide 10-13 N-((3R)-7-(9-oxa-3,7- see see above ++++ ++++ ++++ diazabicyclo[3.3.1]nonan-3-yl)- above 5-fluorochroman-3-yl)-3-amino- 4,6-dimethylthieno[2,3- b]pyridine-2-carboxamide 10-14 (R)-3-amino-N-(5-fluoro-7- see see above ++++ ++ +++ (piperazin-1-yl)chroman-3-yl)-6- above methyl-4- (trifluoromethyl)thieno[2,3- b]pyridine-2-carboxamide 10-15 3-amino-N-[(3R)-5-fluoro-7- see see above + + (piperazin-1-yl)-3,4-dihydro-2H- above 1-benzopyran-3-yl]-N,6- dimethylthieno[2,3-b]pyridine-2- carboxamide 10-16 3-amino-N-[(3S)-5-fluoro-7- see see above + (piperazin-1-yl)-3,4-dihydro-2H- above 1-benzopyran-3-yl]-N,6- dimethylthieno[2,3-b]pyridine-2- carboxamide 11-1 N-((2S)-6-(3,8- see see above ++++ +++ ++ diazabicyclo[3.2.1]octan-3-yl)- above 1,2,3,4-tetrahydronaphthalen-2- yl)-3-amino-6-methylthieno[2,3- b]pyridine-2-carboxamide 11-2 N-((2R)-6-(3,8- see see above +++ ++ + diazabicyclo[3.2.1]octan-3-yl)- above 1,2,3,4-tetrahydronaphthalen-2- yl)-3-amino-6-methylthieno[2,3- b]pyridine-2-carboxamide 11-3 N-((2S)-6-(3,8- see see above +++ ++ ++ diazabicyclo[3.2.1]octan-3-yl)- above 1,2,3,4-tetrahydronaphthalen-2- yl)-3-amino-5-fluoro-6- methylthieno[2,3-b]pyridine-2- carboxamide 11-4 N-((2R)-6-(3,8- see see above ++++ +++ +++ diazabicyclo[3.2.1]octan-3-yl)- above 1,2,3,4-tetrahydronaphthalen-2- yl)-3-amino-5-fluoro-6- methylthieno[2,3-b]pyridine-2- carboxamide 11-5 N-((2S)-6-(3,8- see see above ++++ ++ ++ diazabicyclo[3.2.1]octan-3-yl)- above 1,2,3,4-tetrahydronaphthalen-2- yl)-3-amino-6- methoxythieno[2,3-b]pyridine-2- carboxamide 11-6 N-((2R)-6-(3,8- see see above ++ + + diazabicyclo[3.2.1]octan-3-yl)- above 1,2,3,4-tetrahydronaphthalen-2- yl)-3-amino-6- methoxythieno[2,3-b]pyridine-2- carboxamide 11-7 N-((2S)-6-(3,8- see see above +++ ++ ++ diazabicyclo[3.2.1]octan-3-yl)- above 1,2,3,4-tetrahydronaphthalen-2- yl)-7-amino-3-methylthieno[2,3- b]pyrazine-6-carboxamide 11-8 N-((2R)-6-(3,8- see see above ++ + + diazabicyclo[3.2.1]octan-3-yl)- above 1,2,3,4-tetrahydronaphthalen-2- yl)-7-amino-3-methylthieno[2,3- b]pyrazine-6-carboxamide 11-9 N-((2S)-6-(3,8- see see above ++ + + diazabicyclo[3.2.1]octan-3-yl)- above 1,2,3,4-tetrahydronaphthalen-2- yl)-1-ethyl-1H-pyrrolo[2,3- b]pyridine-5-carboxamide 11-10 N-((2R)-6-(3,8- see see above +++ ++ ++ diazabicyclo[3.2.1]octan-3-yl)- above 1,2,3,4-tetrahydronaphthalen-2- yl)-1-ethyl-1H-pyrrolo[2,3- b]pyridine-5-carboxamide 11-11 (S)-3-amino-N-(8-fluoro-6- see see above ++ + + (piperazin-1-yl)-1,2,3,4- above tetrahydronaphthalen-2-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 11-12 (R)-3-amino-N-(8-fluoro-6- see see above ++++ ++ ++ (piperazin-1-yl)-1,2,3,4- above tetrahydronaphthalen-2-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 11-13 N-((2S)-6-(3,8- see see above ++ + + diazabicyclo[3.2.1]octan-3-yl)-8- above fluoro-1,2,3,4- tetrahydronaphthalen-2-yl)-7- amino-3-methylthieno[2,3- b]pyrazine-6-carboxamide 11-14 N-((2R)-6-(3,8- see see above ++++ +++ ++ diazabicyclo[3.2.1]octan-3-yl)-8- above fluoro-1,2,3,4- tetrahydronaphthalen-2-yl)-7- amino-3-methylthieno[2,3- b]pyrazine-6-carboxamide 11-15 3-amino-6-methyl-N-((3R,4R)-4- see see above + + + methyl-7-(piperazin-1- above yl)chroman-3-yl)thieno[2,3- b]pyridine-2-carboxamide 11-16 3-amino-6-methyl-N-((3R,4S)-4- see see above + + + methyl-7-(piperazin-1- above yl)chroman-3-yl)thieno[2,3- b]pyridine-2-carboxamide 11-17 3-amino-6-methyl-N-((3S,4S)-4- see see above + + + methyl-7-(piperazin-1- above yl)chroman-3-yl)thieno[2,3- b]pyridine-2-carboxamide 11-18 3-amino-6-methyl-N-((3S,4R)-4- see see above ++ + + methyl-7-(piperazin-1- above yl)chroman-3-yl)thieno[2,3- b]pyridine-2-carboxamide 11-19 (S)-7-amino-3-methyl-N-(6- see see above ++ ++ (piperazin-1-yl)-1,2,3,4 above tetrahydronaphthalen-2- yl)thieno[2,3-b]pyrazine-6- carboxamide 11-20 (R)-7-amino-3-methyl-N-(6- see see above ++ + + (piperazin-1-yl)-1,2,3,4- above tetrahydronaphthalen-2- yl)thieno[2,3-b]pyrazine-6- carboxamide 11-21 (S)-3-amino-6-methyl-N-(6- see see above ++ ++ + (piperazin-1-yl)-1,2,3,4- above tetrahydronaphthalen-2- yl)thieno[2,3-b]pyridine-2- carboxamide 11-22 (R)-3-amino-6-methyl-N-(6- see see above +++ ++ ++ (piperazin-1-yl)-1,2,3,4- above tetrahydronaphthalen-2- yl)thieno[2,3-b]pyridine-2- carboxamide 11-23 N-((2R)-6-(3,8- see see above ++ + + diazabicyclo[3.2.1]octan-3-yl)- above 1,2,3,4-tetrahydronaphthalen-2- yl)-7-ethyl-7H-pyrrolo[2,3- c]pyridazine-3-carboxamide 11-24 N-((2S)-6-(3,8- see see above ++ + + diazabicyclo[3.2.1]octan-3-yl)- above 1,2,3,4-tetrahydronaphthalen-2- yl)-7-ethyl-7H-pyrrolo[2,3- c]pyridazine-3-carboxamide 11-25 7-amino-3-methyl-N-((S)-6-((S)- see see above +++ ++ ++ 3-(methylamino)pyrrolidin-1-yl)- above 1,2,3,4-tetrahydronaphthalen-2- yl)thieno[2,3-b]pyrazine-6- carboxamide 11-26 7-amino-3-methyl-N-((R)-6-((S)- see see above + + + 3-(methylamino)pyrrolidin-1-yl)- above 1,2,3,4-tetrahydronaphthalen-2- yl)thieno[2,3-b]pyrazine-6- carboxamide 11-27 7-amino-3-methyl-N-((S)-6-((R)- see see above +++ ++ ++ 3-(methylamino)pyrrolidin-1-yl)- above 1,2,3,4-tetrahydronaphthalen-2- yl)thieno[2,3-b]pyrazine-6- carboxamide 11-28 7-amino-3-methyl-N-((R)-6-((R)- see see above ++ + + 3-(methylamino)pyrrolidin-1-yl)- above 1,2,3,4-tetrahydronaphthalen-2- yl)thieno[2,3-b]pyrazine-6- carboxamide 11-29 N-((S)-6-((1S,4S)-2,5- see see above +++ ++ ++ diazabicyclo[2.2.1]heptan-2-yl)- above 1,2,3,4-tetrahydronaphthalen-2- yl)-7-amino-3-methylthieno[2,3- b]pyrazine-6-carboxamide 11-30 N-((R)-6-((1S,4S)-2,5- see see above ++ ++ ++ diazabicyclo[2.2.1]heptan-2-yl)- above 1,2,3,4-tetrahydronaphthalen-2- yl)-7-amino-3-methylthieno[2,3- b]pyrazine-6-carboxamide 11-31 N-((S)-6-((1R,4R)-2,5- see see above +++ ++ ++ diazabicyclo[2.2.1]heptan-2-yl)- above 1,2,3,4-tetrahydronaphthalen-2- yl)-7-amino-3-methylthieno[2,3- b]pyrazine-6-carboxamide 11-32 N-((R)-6-((1R,4R)-2,5- see see above ++ ++ ++ diazabicyclo[2.2.1]heptan-2-yl)- above 1,2,3,4-tetrahydronaphthalen-2- yl)-7-amino-3-methylthieno[2,3- b]pyrazine-6-carboxamide 11-33 (S)-6-amino-2-methyl-N-(6- see see above ++ + + (piperazin-1-yl)-1,2,3,4- above tetrahydronaphthalen-2- yl)thieno[2,3-dithiazole-5- carboxamide 11-34 (R)-6-amino-2-methyl-N-(6- see see above +++ ++ + (piperazin-1-yl)-1,2,3,4- above tetrahydronaphthalen-2- yl)thieno[2,3-dithiazole-5- carboxamide 11-35 N-((2S)-6-(3,6- see see above ++++ ++ ++ diazabicyclo[3.1.1]heptan-6-yl)- above 1,2,3,4-tetrahydronaphthalen-2- yl)-3-amino-6-methylthieno[2,3- b]pyridine-2-carboxamide 11-36 N-((2R)-6-(3,6- see see above ++ ++ ++ diazabicyclo[3.1.1]heptan-6-yl)- above 1,2,3,4-tetrahydronaphthalen-2- yl)-3-amino-6-methylthieno[2,3- b]pyridine-2-carboxamide 11-37 (R)-7-amino-N-(8-fluoro-6- see see above ++ + + (piperazin-1-yl)-1,2,3,4- above tetrahydronaphthalen-2-yl)-3- methylthieno[2,3-b]pyrazine-6- carboxamide 11-38 (S)-7-amino-N-(8-fluoro-6- see see above +++ +++ ++ (piperazin-1-yl)-1,2,3,4- above tetrahydronaphthalen-2-yl)-3- methylthieno[2,3-b]pyrazine-6- carboxamide 11-39 N-((2S)-6-(9-oxa-3,7- see see above ++ ++ + diazabicyclo[3.3.1]nonan-3-yl)- above 8-fluoro-1,2,3,4- tetrahydronaphthalen-2-yl)-3- amino-6-methylthieno[2,3- b]pyridine-2-carboxamide 11-40 N-((2R)-6-(9-oxa-3,7- see see above ++++ +++ diazabicyclo[3.3.1]nonan-3-yl)- above 8-fluoro-1,2,3,4- tetrahydronaphthalen-2-yl)-3- amino-6-methylthieno[2,3- b]pyridine-2-carboxamide 12-1 N-((2S)-6-(3,8- see see above ++ + + diazabicyclo[3.2.1]octan-3-yl)- above 1,2,3,4-tetrahydronaphthalen-2- yl)-6-amino-2-methylthieno[2,3- d]thiazole-5-carboxamide 12-2 N-((2R)-6-(3,8- see see above ++ ++ diazabicyclo[3.2.1]octan-3-yl)- above 1,2,3,4-tetrahydronaphthalen-2- yl)-6-amino-2-methylthieno[2,3- d]thiazole-5-carboxamide 13-1 N-((3R)-7-(3,8- see see above ++++ ++++ +++ diazabicyclo[3.2.1]octan-3-yl)- above 5,8-difluorochroman-3-yl)-3- amino-6-methylthieno[2,3- b]pyridine-2-carboxamide 13-2 N-((3S)-7-(3,8- see see above ++ + + diazabicyclo[3.2.1]octan-3-yl)- above 5,8-difluorochroman-3-yl)-3- amino-6-methylthieno[2,3- b]pyridine-2-carboxamide 13-3 N-((3R)-7-(3,8- see see above ++ + + diazabicyclo[3.2.1]octan-3-yl)- above 5,6-difluorochroman-3-yl)-3- amino-6-methylthieno[2,3- b]pyridine-2-carboxamide 13-4 N-((3S)-7-(3,8- see see above ++++ ++++ +++ diazabicyclo[3.2.1]octan-3-yl)- above 5,6-difluorochroman-3-yl)-3- amino-6-methylthieno[2,3- b]pyridine-2-carboxamide 13-5 (R)-3-amino-N-(6-chloro-7- see see above + + + (piperazin-1-yl)chroman-3-yl)-6- above methylthieno[2,3-b]pyridine-2- carboxamide 13-6 (S)-3-amino-N-(6-chloro-7- see see above ++++ +++ +++ (piperazin-1-yl)chroman-3-yl)-6- above methylthieno[2,3-b]pyridine-2- carboxamide 13_7 (R)-3-amino-N-(8-chloro-7- see see above ++++ +++ +++ (piperazin-1-yl)chroman-3-yl)-6- above methylthieno[2,3-b]pyridine-2- carboxamide 13-8 (S)-3-amino-N-(8-chloro-7- see see above ++ + + (piperazin-1-yl)chroman-3-yl)-6- above methylthieno[2,3-b]pyridine-2- carboxamide 14-1 N-((2R)-6-(3,8- see see above ++++ ++++ +++ diazabicyclo[3.2.1]octan-3-yl)-5- above cyano-1,2,3,4- tetrahydronaphthalen-2-yl)-3- amino-6-methylthieno[2,3- b]pyridine-2-carboxamide 14-2 N-((2S)-6-(3,8- see see above +++ ++ + diazabicyclo[3.2.1]octan-3-yl)-5- above cyano-1,2,3,4- tetrahydronaphthalen-2-yl)-3- amino-6-methylthieno[2,3- b]pyridine-2-carboxamide 14-3 N-((2R)-6-(3,8- see see above ++ ++ + diazabicyclo[3.2.1]octan-3-yl)-7- above cyano-1,2,3,4- tetrahydronaphthalen-2-yl)-3- amino-6-methylthieno[2,3- b]pyridine-2-carboxamide 14-4 N-((2S)-6-(3,8- see see above ++++ ++++ +++ diazabicyclo[3.2.1]octan-3-yl)-7- above cyano-1,2,3,4- tetrahydronaphthalen-2-yl)-3- amino-6-methylthieno[2,3- b]pyridine-2-carboxamide 14-5 N-((2R)-6-(3,8- see see above ++++ +++ +++ diazabicyclo[3.2.1]octan-3-yl)-5- above cyano-1,2,3,4- tetrahydronaphthalen-2-yl)-7- amino-3-methylthieno[2,3- b]pyrazine-6-carboxamide 14-6 N-((2S)-6-(3,8- see see above ++ + + diazabicyclo[3.2.1]octan-3-yl)-5- above cyano-1,2,3,4- tetrahydronaphthalen-2-yl)-7- amino-3-methylthieno[2,3- b]pyrazine-6-carboxamide 14-7 N-((2R)-6-(3,8- see see above ++ ++ + diazabicyclo[3.2.1]octan-3-yl)-7- above cyano-1,2,3,4- tetrahydronaphthalen-2-yl)-7- amino-3-methylthieno[2,3- b]pyrazine-6-carboxamide 14-8 N-((2S)-6-(3,8- see see above ++++ ++++ +++ diazabicyclo[3.2.1]octan-3-yl)-7- above cyano-1,2,3,4- tetrahydronaphthalen-2-yl)-7- amino-3-methylthieno[2,3- b]pyrazine-6-carboxamide 14-9 (R)-3-amino-N-(5-cyano-8- see see above ++ + + fluoro-6-(piperazin-1-yl)-1,2,3,4- above tetrahydronaphthalen-2-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 14-10 (S)-3-amino-N-(5-cyano-8- see see above ++++ +++ ++ fluoro-6-(piperazin-1-yl)-1,2,3,4- above tetrahydronaphthalen-2-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 14-11 (R)-7-amino-N-(5-cyano-8- see see above ++++ ++ fluoro-6-(piperazin-1-yl)-1,2,3,4- above tetrahydronaphthalen-2-yl)-3- methylthieno[2,3-b]pyrazine-6- carboxamide 14-12 (S)-7-amino-N-(5-cyano-8- see see above ++ + fluoro-6-(piperazin-1-yl)-1,2,3,4- above tetrahydronaphthalen-2-yl)-3- methylthieno[2,3-b]pyrazine-6- carboxamide 14-13 (R)-6-amino-N-(5-cyano-8- see see above ++ + fluoro-6-(piperazin-1-yl)-1,2,3,4- above tetrahydronaphthalen-2-yl)-2- methylthieno[2,3-d]thiazole-5- carboxamide 14-14 (S)-6-amino-N-(5-cyano-8- see see above ++++ ++ fluoro-6-(piperazin-1-yl)-1,2,3,4- above tetrahydronaphthalen-2-yl)-2- methylthieno[2,3-d]thiazole-5- carboxamide 14-15 3-amino-N-[(2S)-5-cyano-8- see see above ++++ ++++ fluoro-6-{9-oxa-3,7- above diazabicyclo[3.3.1]nonan-3-yl}- 1,2,3,4-tetrahydronaphthalen-2- yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide 14-16 3-amino-N-[(2R)-5-cyano-8- see see above +++ ++ fluoro-6-{9-oxa-3,7- above diazabicyclo[3.3.1]nonan-3-yl}- 1,2,3,4-tetrahydronaphthalen-2- yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide 14-17 3-amino-N-[(2S)-5-cyano-6- see see above ++++ ++++ {3,8-diazabicyclo[3.2.1]octan-3- above yl}-8-fluoro-1,2,3,4- tetrahydronaphthalen-2-yl]-6- methylthieno[2,3-b]pyridine-2- carboxamide 14-18 3-amino-N-[(2R)-5-cyano-6- see see above +++ + {3,8-diazabicyclo[3.2.1]octan-3- above yl}-8-fluoro-1,2,3,4- tetrahydronaphthalen-2-yl]-6- methylthieno[2,3-b]pyridine-2- carboxamide 14-19 7-amino-N-[(2S)-5-cyano-6- see see above ++++ +++ {3,8-diazabicyclo[3.2.1]octan-3- above yl}-8-fluoro-1,2,3,4- tetrahydronaphthalen-2-yl]-3- methylthieno[2,3-b]pyrazine-6- carboxamide 14-20 7-amino-N-[(2R)-5-cyano-6- see see above ++ + {3,8-diazabicyclo[3.2.1]octan-3- above yl}-8-fluoro-1,2,3,4- tetrahydronaphthalen-2-yl]-3- methylthieno[2,3-b]pyrazine-6- carboxamide 14-21 6-amino-N-[(2S)-5-cyano-6- see see above ++++ +++ {3,8-diazabicyclo[3.2.1]octan-3- above yl}-8-fluoro-1,2,3,4- tetrahydronaphthalen-2-yl]-2- methylthieno[2,3-d][1, 3]thiazole- 5-carboxamide 14-22 6-amino-N-[(2R)-5-cyano-6- see see above ++ + {3,8-diazabicyclo[3.2.1]octan-3- above yl}-8-fluoro-1,2,3,4- tetrahydronaphthalen-2-yl]-2- methylthieno[2,3-d][1, 3]thiazole- 5-carboxamide 14-23 3-amino-N-[(2S)-6-[(3S,4S)-3- see see above ++++ ++ amino-4-methoxypyrrolidin-1- above yl]-5-cyano-8-fluoro-1,2,3,4- tetrahydronaphthalen-2-yl]-6- methylthieno[2,3-b]pyridine-2- carboxamide 14-24 3-amino-N-[(2R)-6-[(3S,4S)-3- see see above ++ + amino-4-methoxypyrrolidin-1- above yl]-5-cyano-8-fluoro-1,2,3,4- tetrahydronaphthalen-2-yl]-6- methylthieno[2,3-b]pyridine-2- carboxamide 15-1 (R)-3-amino-6-methyl-N-(3- see see above + + + (piperazin-1-yl)-5,6,7,8- above tetrahydroquinolin-7- yl)thieno[2,3-b]pyridine-2- carboxamide 15-2 (S)-3-amino-6-methyl-N-(3- see see above ++ + + (piperazin-1-yl)-5,6,7,8- above tetrahydroquinolin-7- yl)thieno[2,3-b]pyridine-2- carboxamide 16 (R)-3-amino-6-methyl-N-(7- see see above ++++ ++ ++ (piperazin-1-yl)-3,4-dihydro-2H- above pyrano[3,2-c]pyridin-3- yl)thieno[2,3-b]pyridine-2- carboxamide 17 N-((3R)-7-(3,8- see see above ++++ +++ diazabicyclo[3.2.1]octan-3-yl)-5- above fluoro-3,4-dihydro-2H- pyrano[3,2-c]pyridin-3-yl)-3- amino-6-methylthieno[2,3- b]pyridine-2-carboxamide 18 N-((3R)-7-(3,8- see see above ++++ +++ diazabicyclo[3.2.1]octan-3-yl)-8- above fluoro-3,4-dihydro-2H- pyrano[3,2-c]pyridin-3-yl)-3- amino-6-methylthieno[2,3- b]pyridine-2-carboxamide 19 (R)-3-amino-6-methyl-N-(7- see see above +++ ++ (piperazin-1-yl)-3,4-dihydro-2H- above pyrano[2,3-b]pyridin-3- yl)thieno[2,3-b]pyridine-2- carboxamide 20 (R)-3-amino-N-(6-fluoro-7- see see above +++ ++ above (piperazin-1-yl)-3,4-dihydro-2H- above pyrano[2,3-b]pyridin-3-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 21-1 N-((2R)-6-(3,8- see see above +++ ++ + diazabicyclo[3.2.1]octan-3-yl)-5- above fluoro-1,2,3,4- tetrahydronaphthalen-2-yl)-3- amino-6-methylthieno[2,3- b]pyridine-2-carboxamide 21-2 N-((2S)-6-(3,8- see see above ++++ ++ ++ diazabicyclo[3.2.1]octan-3-yl)-5- above fluoro-1,2,3,4- tetrahydronaphthalen-2-yl)-3- amino-6-methylthieno[2,3- b]pyridine-2-carboxamide 21-3 N-((2R)-6-(3,8- see see above ++++ ++++ +++ diazabicyclo[3.2.1]octan-3-yl)-7- above fluoro-1,2,3,4- tetrahydronaphthalen-2-yl)-3- amino-6-methylthieno[2,3- b]pyridine-2-carboxamide 21-4 N-((2S)-6-(3,8- see see above ++ ++ + diazabicyclo[3.2.1]octan-3-yl)-7- above fluoro-1,2,3,4- tetrahydronaphthalen-2-yl)-3- amino-6-methylthieno[2,3- b]pyridine-2-carboxamide 21-5 (R)-3-amino-N-(5-fluoro-6- see see above ++++ ++++ +++ (piperazin-1-yl)-1,2,3,4- above tetrahydronaphthalen-2-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 21-6 (S)-3-amino-N-(5-fluoro-6- see see above ++ ++ + (piperazin-1-yl)-1,2,3,4- above tetrahydronaphthalen-2-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 21-7 (R)-3-amino-N-(7-fluoro-6- see see above +++ +++ ++ (piperazin-1-yl)-1,2,3,4- above tetrahydronaphthalen-2-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 21-8 (S)-3-amino-N-(7-fluoro-6- see see above ++ + + (piperazin-1-yl)-1,2,3,4- above tetrahydronaphthalen-2-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 21-9 (S)-7-amino-N-(5-fluoro-6- see see above +++ ++ ++ (piperazin-1-yl)-1,2,3,4- above tetrahydronaphthalen-2-yl)-3- methylthieno[2,3-b]pyrazine-6- carboxamide 21-10 (R)-7-amino-N-(5-fluoro-6- see see above + + + (piperazin-1-yl)-1,2,3,4- above tetrahydronaphthalen-2-yl)-3- methylthieno[2,3-b]pyrazine-6- carboxamide 21-11 (S)-7-amino-N-(7-fluoro-6- see see above ++ ++ + (piperazin-1-yl)-1,2,3,4- above tetrahydronaphthalen-2-yl)-3- methylthieno[2,3-b]pyrazine-6- carboxamide 21-12 (R)-7-amino-N-(7-fluoro-6- see see above ++++ ++++ ++ (piperazin-1-yl)-1,2,3,4- above tetrahydronaphthalen-2-yl)-3- methylthieno[2,3-b]pyrazine-6- carboxamide 22-1 (S)-3-amino-N-(5,8-difluoro-6- see see above ++ ++ + (piperazin-1-yl)-1,2,3,4- above tetrahydronaphthalen-2-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 22-2 (R)-3-amino-N-(5,8-difluoro-6- see see above ++++ +++ +++ (piperazin-1-yl)-1,2,3,4- above tetrahydronaphthalen-2-yl)-6- methylthieno[2,3-b]pyridine-2- carboxamide 22-3 N-((2S)-6-(9-oxa-3,7- see see above ++ + diazabicyclo[3.3.1]nonan-3-yl)- above 5,8-difluoro-1,2,3,4- tetrahydronaphthalen-2-yl)-3- amino-6-methylthieno[2,3- b]pyridine-2-carboxamide 22-4 N-((2R)-6-(9-oxa-3,7- see see above ++++ ++++ diazabicyclo[3.3.1]nonan-3-yl)- above 5,8-difluoro-1,2,3,4- tetrahydronaphthalen-2-yl)-3- amino-6-methylthieno[2,3- b]pyridine-2-carboxamide 22-5 3-amino-N-[(2S)-6-{3,8- see see above ++++ ++++ diazabicyclo[3.2.1]octan-3-yl}- above 5,8-difluoro-1,2,3,4- tetrahydronaphthalen-2-yl]-6- methylthieno[2,3-b]pyridine-2- carboxamide 22-6 3-amino-N-[(2R)-6-{3,8- see see above ++ + diazabicyclo[3.2.1]octan-3-yl}- above 5,8-difluoro-1,2,3,4- tetrahydronaphthalen-2-yl]-6- methylthieno[2,3-b]pyridine-2- carboxamide 23-1 7-amino-N-[(6S)-2-[(3S,4S)-3- see see above ++ + amino-4-methoxypyrrolidin-1- above yl]-5,6,7,8-tetrahydroquinolin-6- yl]-3-methylthieno[2,3- b]pyrazine-6-carboxamide 23-2 7-amino-N-[(6R)-2-[(3S,4S)-3- see see above + + amino-4-methoxypyrrolidin-1- above yl]-5,6,7,8-tetrahydroquinolin-6- yl]-3-methylthieno[2,3- b]pyrazine-6-carboxamide 23-3 3-amino-N-[(6S)-2-[(3S,4S)-3- see see above +++ + amino-4-methoxypyrrolidin-1- above yl]-5,6,7,8-tetrahydroquinolin-6- yl]-4,6-dimethylthieno[2,3- b]pyridine-2-carboxamide 23-4 3-amino-N-[(6S)-2-[(3S,4S)-3- see see above +++ + amino-4-methoxypyrrolidin-1- above yl]-5,6,7,8-tetrahydroquinolin-6- yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide 23-5 3-amino-N-[(6R)-2-[(3S,4S)-3- see see above ++ + amino-4-methoxypyrrolidin-1- above yl]-5,6,7,8-tetrahydroquinolin-6- yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide 23-6 7-amino-3-methyl-N-[(6S)-2- see see above +++ ++ (piperazin-1-yl)-5,6,7,8- above tetrahydroquinolin-6- yl]thieno[2,3-b]pyrazine-6- carboxamide 23-7 3-amino-6-methyl-N-[(6S)-2- see see above ++++ ++ (piperazin-1-yl)-5,6,7,8- above tetrahydroquinolin-6- yl]thieno[2,3-b]pyridine-2- carboxamide 23-8 3-amino-6-methyl-N-[(6R)-2- see see above +++ + (piperazin-1-yl)-5,6,7,8- above tetrahydroquinolin-6- yl]thieno[2,3-b]pyridine-2- carboxamide 23-9 6-amino-2-methyl-N-[(6S)-2- see see above +++ + (piperazin-1-yl)-5,6,7,8- above tetrahydroquinolin-6- yl]thieno[2,3-d][1,3]thiazole-5- carboxamide 23-10 3-amino-N-[(6S)-2-{3,6- see see above ++ ++ diazabicyclo[3.1.1]heptan-3-yl} above 5,6,7,8-tetrahydroquinolin-6-yl]- 6-methylthieno[2,3-b]pyridine-2- carboxamide 23-11 7-amino-N-[(6S)-2-{3,6- see see above ++ ++ diazabicyclo[3.1.1]heptan-3-yl} above 5,6,7,8-tetrahydroquinolin-6-yl]- 3-methylthieno[2,3-b]pyrazine- 6-carboxamide 23-12 3-amino-N-[(6S)-2-{3,8- see see above ++++ ++ diazabicyclo[3.2.1]octan-3-yl} above 5,6,7,8-tetrahydroquinolin-6-yl] 6-methylthieno[2,3-b]pyridine-2- carboxamide 23-13 7-amino-N-[(6S)-2-{3,8- see above ++++ ++ diazabicyclo[3.2.1]octan-3-yl}- see above 5,6,7,8-tetrahydroquinolin-6-yl] 3-methylthieno[2,3-b]pyrazine- 6-carboxamide 23-14 3-amino-4,6-dimethyl-N-[(6S)-2- see see above ++++ ++ (piperazin-1-yl)-5,6,7,8- above tetrahydroquinolin-6- yl]thieno[2,3-b]pyridine-2- carboxamide 23-15 3-amino-6-methyl-N-[(6S)-2- see see above ++++ ++ [(3S)-3-methylpiperazin-1-yl]- above 5,6,7,8-tetrahydroquinolin-6- yl]thieno[2,3-b]pyridine-2- carboxamide 23-16 3-amino-6-methyl-N-[(6S)-2- see see above ++++ ++ [(3R)-3-methylpiperazin-1-yl] above 5,6,7,8-tetrahydroquinolin-6- yl]thieno[2,3-b]pyridine-2- carboxamide 23-17 3-amino-N-[(6S)-4-fluoro-2- see see above ++++ ++ (piperazin-1-yl)-5,6,7,8- above tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2- carboxamide 23-18 3-amino-N-[(6S)-2-{3,8- see see above ++++ ++ diazabicyclo[3.2.1]octan-3-yl}-4- above fluoro-5,6,7,8- tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2- carboxamide 24-1 3-amino-N-[(6S)-2-[(3R,4R)-3- see see above +++ + amino-4- above (methoxymethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]- 6-methylthieno[2,3-b]pyridine-2- carboxamide 24-2 3-amino-N-[(6S)-2-[(3S,4S)-3- see see above +++ ++ amino-4- above (methoxymethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]- 6-methylthieno[2,3-b]pyridine-2- carboxamide 25 3-amino-N-[(6S)-2-[(3S,4R)-3- amino-4- (difluoromethyl)pyrrolidin-1-yl]- see see above +++ ++ 5,6,7,8-tetrahydroquinolin-6-yl]- above 6-methylthieno[2,3-b]pyridine-2- carboxamide 26-1 3-amino-N-[(6S)-2-[(3S,4R)-3- see see above +++ (methoxymethyl)-4- above (methylamino)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]- 6-methylthieno[2,3-b]pyridine-2- carboxamide 26-2 3-amino-N-[(6S)-2-[(3R,4S)-3- see see above +++ (methoxymethyl)-4- above (methylamino)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]- 6-methylthieno[2,3-b]pyridine-2- carboxamide 27-1 3-amino-N-[(6S)-2-[(3R,4R)-3- see see above +++ amino-4- above (fluoromethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]- 6-methylthieno[2,3-b]pyridine-2- carboxamide 27-2 3-amino-N-[(6S)-2-[(3S,4S)-3- see see above +++ amino-4- above (fluoromethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]- 6-methylthieno[2,3-b]pyridine-2- carboxamide 28-1 3-amino-N-[(6S)-2-[(3S,4S)-3- see see above ++ amino-4-(2- above methoxyethoxy)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]- 6-methylthieno[2,3-b]pyridine-2- carboxamide 28-2 3-amino-N-[(6S)-2-[(3R,4R)-3- see see above ++ amino-4-(2- methoxyethoxy)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]- above 6-methylthieno[2,3-b]pyridine-2- carboxamide 29-1 3-amino-N-[(6S)-2-[(9S)-9- see see above ++ amino-1,4-dioxa-7- above azaspiro[4.4]nonan-7-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]- 6-methylthieno[2,3-b]pyridine-2- carboxamide 29-2 3-amino-N-[(6S)-2-[(9R)-9- see see above ++ amino-1,4-dioxa-7- azaspiro[4.4]nonan-7-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]- above 6-methylthieno[2,3-b]pyridine-2- carboxamide 30-1 3-amino-N-[(6S)-3-fluoro-2- see see above ++++ ++ (piperazin-1-yl)-5,6,7,8- above tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2- carboxamide 30-2 3-amino-N-[(6R)-3-fluoro-2- see see above ++ + (piperazin-1-yl)-5,6,7,8- above tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2- carboxamide 31-1 3-amino-N-[(6S)-2-[(3S,4S)-3- see see above +++ amino-4-(propan-2- above yloxy)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinazolin-6-yl]-4,6- dimethylthieno[2,3-b]pyridine-2- carboxamide 31-2 3-amino-N-[(6R)-2-[(3S,4S)-3- see see above + amino-4-(propan-2- above yloxy)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinazolin-6-yl]-4,6- dimethylthieno[2,3-b]pyridine-2- carboxamide 31-3 3-amino-6-methyl-N-[(6′S)-2- see see above +++ + (piperazin-1-yl)-6′,7′-dihydro- above 5′H-spiro[cyclopropane-1,8′- quinoline]-6′-yl]thieno[2,3- b]pyridine-2-carboxamide 31-4 3-amino-6-methyl-N-[(6′R)-2′- see see above ++++ ++ (piperazin-1-yl)-6′,7′-dihydro- above 5′H-spiro[cyclopropane-1,8′- quinoline]-6′-yl]thieno[2,3- b]pyridine-2-carboxamide 32-1 3-amino-6-methyl-N-[(7S)-3- see see above +++ (piperazin-1-yl)-5,6,7,8- above tetrahydroisoquinolin-7- yl]thieno[2,3-b]pyridine-2- carboxamide 32-2 3-amino-6-methyl-N-[(7R)-3- see see above ++ (piperazin-1-yl)-5,6,7,8- above tetrahydroisoquinolin-7- yl]thieno[2,3-b]pyridine-2- carboxamide 33-1 3-amino-N-[(3R)-5-fluoro-7- see see above ++++ ++ (piperazin-1-yl)-3,4-dihydro(4,4- above Â²Hâ,,)-2H-1-benzopyran-3-yl]- 6-methylthieno[2,3-b]pyridine-2- carboxamide 33-2 3-amino-N-[(3S)-5-fluoro-7- see see above ++ + (piperazin-1-yl)-3,4-dihydro(4,4- above Â²Hâ,,)-2H-1-benzopyran-3-yl]- 6-methylthieno[2,3-b]pyridine-2- carboxamide 33-3 3-amino-N-[(3R)-7-[(1R,6S)-3,8- see see above ++++ +++ diazabicyclo[4.2.0]octan-8-yl]- above 3,4-dihydro-2H-1-benzopyran-3- yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide 33-4 3-amino-N-[(3R)-7-[(1S,6R)-3,8- see see above ++++ ++ diazabicyclo[4.2.0]octan-8-yl]- above 3,4-dihydro-2H-1-benzopyran-3- yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide 34 3-amino-N-[(3R)-7-(4-cyano- see see above ++++ ++++ 1,1-dioxo-1λ6-thian-4-yl)-3,4- above dihydro-2H-1-benzopyran-3-yl]- 6-methylthieno[2,3-b]pyridine-2- carboxamide 35 3-amino-6-methyl-N-[(3R)-5,6,8- see see above ++++ +++ trifluoro-7-(piperazin-1-yl)-3,4- above dihydro-2H-1-benzopyran-3- yl]thieno[2,3-b]pyridine-2- carboxamide 36 (R)-7-amino-2-ethyl-N-(7- 439 (DMSO-d6 400 MHz) δ(ppm): 8.68 (s, ++ ++ ++ (piperazin-1-yl)chroman-3- 1H), 7.83-7.81 (br s, 1H), 6.95-6.91 (m, yl)thieno[2,3-b]pyrazine-6- 3H), 6.52 (dd, J = 2.4, 8.4 Hz, 1H), 6.32 carboxamide (s, 1H), 4.35-4.26 (m, 1H), 4.19-4.16 (m, 1H), 3.85-3.80 (m, 1H), 3.46-3.33 (m, 1H), 3.03-3.01 (m, 4H), 2.98-2.94 (m, 2H), 2.93-2.87 (m, 6H), 1.37-1.35 (m, 3H). 37 (S)-7-amino-2-ethyl-N-(7- 439 (DMSO-d6, 400 MHz) δ(ppm): 8.68 (s, + + + (piperazin-1-yl)chroman-3- 1H), 7.83-7.81 (br s, 1H), 6.94-6.91 (m, yl)thieno[2,3-b]pyrazine-6- 3H), 6.51 (dd, J = 2.4, 8.4 Hz, 1H), 6.30 carboxamide (s, 1H), 4.35-4.26 (m, 1H), 4.19-4.15 (m, 1H), 3.85-3.80 (m, 1H), 3.44-3.33 (m, 1H), 3.03-2.93 (m, 6H), 2.88-2.81 (m, 6H), 1.37-1.35 (m, 3H). 38 (R)-1-(difluoromethyl)-N-(7- 428 (CD2Cl2, 300 MHz) δ(ppm): 8.66-8.71 ++ + + (piperazin-1-yl)chroman-3-yl)- (m, 1 H), 8.29-8.33 (m, 1 H), 7.86 (t, J = 1H-pyrrolo[2,3-b]pyridine-5- 60 Hz, 1 H), 7.58 (d, J = 3.81 Hz, 1 H), carboxamide 6.95 (d, J = 8.50 Hz, 1 H), 6.72 (dd, J = 3.81, 0.59 Hz, 1 H), 6.52 (dd, J = 8.50, 2.64 Hz, 1 H), 6.46 (br d, J = 7.62 Hz, 1 H), 6.39 (d, J = 2.64 Hz, 1 H), 4.60-4.68 (m, 1 H), 4.16-4.28 (m, 2 H), 3.10-3.20 (m, 2 H), 3.02-3.08(m, 3H) 2.92-2.99 (m, 3 H), 2.77-2.86 (m, 2H) 39 (S)-1-(difluoromethyl)-N-(7- 428 (CD2Cl2, 300 MHz) δ(ppm): 8.69 (d, J = + + + (piperazin-1-yl)chroman-3-yl)- 1.76 Hz, 1 H), 8.31 (d, J = 2.05 Hz, 1 H), 1H-pyrrolo[2,3-b]pyridine-5- 7.86 (t, J = 60 Hz, 1 H), 7.58 (d, J = 3.81 carboxamide Hz, 1 H), 6.95 (d, J = 8.50 Hz, 1 H), 6.72 (dd, J = 4.10, 0.59 Hz, 1 H), 6.52 (dd, J = 8.35, 2.49 Hz, 1 H), 6.46 (br d, J = 7.92 Hz, 1 H), 6.39 (d, J = 2.64 Hz, 1 H), 4.59-4.69 (m, 1 H), 4.15-4.29 (m, 2 H), 3.10-3.21 (m, 2 H), 3.02-3.09 (m, 3 H), 2.92-3.00 (m, 3H), 2.76-2.87 (m, 2 H) 40 N-((3R)-7-(3,8- 469 (MeOH-d4, 300 MHz) δ(ppm): 8.57 (s, ++++ +++ +++ diazabicyclo[3.2.1]octan-3-yl)-6- 1H), 6.80 (d, J = 12.9 Hz, 1H), 6.42(d, J = fluorochroman-3-yl)-7-amino-3- 7.8 Hz, 1H), 4.57-4.43 (m, 2H), 4.25- methylthieno[2,3-b]pyrazine-6- 4.21 (m, 1H), 3.96-3.89 (m, 1H), 3.82- carboxamide 3.78 (m, 2H), 3.26-3.25 (m,1H), 3.07- 2.83 (m, 4H), 2.67 (s, 3H), 2.13-2.09 (m, 1H), 1.97-1.94 (m, 2H). 41 N-((3S)-7-(3,8- 469 (MeOH-d4, 300 MHz) δ(ppm): 8.57 (s, ++ + + diazabicyclo[3.2.1]octan-3-yl)-6- 1H), 6.80 (d, J = 12.9 Hz, 1H), 6.42 (d, J = fluorochroman-3-yl)-7-amino-3- 7.8 Hz, 1H), 4.57-4.43 (m, 2H), 4.25- methylthieno[2,3-b]pyrazine-6- 4.20 (m, 1H), 3.96-3.89 (m, 1H), 3.82- carboxamide 3.78 (m, 2H), 3.26-3.25 (m, 1H), 3.03- 2.83 (m, 4H), 2.67 (s, 3H), 2.13-2.09 (m, 2H), 1.96-1.93 (m, 2H). 42 3-amino-((S)-7-((3aS,6aS)- 450 (MeOH-d4, 300 MHz) δ(ppm): 8.20 (d, J = ++ ++ hexahydropyrrolo[3,4-c]pyrrol- 8.4 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 2(1H)-yl)chroman-3-yl)-6- 6.88 (d, J = 8.4 Hz, 1H), 6.16 (dd, J = methylthieno[2,3-b]pyridine-2- 2.4, 8.4 Hz, 1H), 6.00 (s, 1H), 4.48-4.37 carboxamide (m, 1H), 4.24-4.21 (m, 1H), 3.92-3.87 (m, 1H), 3.63-3.45 (m, 2H), 3.41-3.35 (m, 2H), 3.14-3.08 (m, 2H), 3.02-2.78 (m, 4H), 2.63 (s, 3H), 2.46-2.38 (m, 2H). 43 3-amino-N-((R)-7-((3aR,6aR)- 450 (MeOH-d4, 300 MHz) δ(ppm): 8.10 (d, J = ++ + + hexahydropyrrolo[3,4-c]pyrrol- 8.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 2(1H)-yl)chroman-3-yl)-6- 6.79 (d, J = 8.4 Hz, 1H), 6.06 (dd, J = methylthieno[2,3-b]pyridine-2- 2.4, 8.4 Hz, 1H), 5.9 (s, 1H), 4.38-4.27 carboxamide (m, 1H), 4.16-4.08 (m, 1H), 3.81-3.78 (m, 1H), 3.38-3.33 (m, 2H), 3.28-3.24 (m, 2H), 3.02-2.97 (m, 2H), 2.92-2.68 (m, 4H), 2.56 (s, 3H), 2.38-2.27 (m, 2H). 44 3-amino-N-((S)-7-((3aR,6aR)- 450 (MeOH-d4, 300 MHz) δ(ppm): 820 (d, J = + + + hexahydropyrrolo[3,4-c]pyrrol- 8.4 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 2(1H)-yl)chroman-3-yl)-6- 6.89 (d, J = 8.4 Hz, 1H), 6.16 (dd, J = methylthieno[2,3-b]pyridine-2- 2.4, 8.4 Hz, 1H), 6.00 (s, 1H), 4.48-4.37 carboxamide (m, 1H), 4.24-4.21 (m, 1H), 3.92-3.87 (m, 1H), 3.63-3.45 (m, 2H), 3.41-3.35 (m, 2H), 3.14-3.08 (m, 2H), 3.02-2.78 (m, 4H), 2.63 (s, 3H), 2.48-2.38 (m, 2H). 45 (R)-6-amino-2-cyclopropyl-N-(7- 456 (DMSO-d6, 300 MHz) δ(ppm): 7.40 (br +++ ++ ++ (piperazin-1-yl)chroman-3- s, 1H), 7.11 (br s, 2H), 6.91 (d, J = 8.4 yl)thieno[2,3-dithiazole-5- Hz, 1H), 6.49 (dd, J = 2.4, 8.4 Hz, 1H), carboxamide 6.29 (s, 1H), 4.24-4.11(m, 2H), 3.77 (t, J = 9.9 Hz, 1H), 3.00-2.97 (m, 4H), 2.84- 2.82 (m, 6H), 2.54-2.51 (m, 1H), 1.23- 1.18 (m, 3H), 1.11-1.09 (m, 2H). 46 N-((3S)-7-(3 8- 474 (MeOH-d4, 300 MHz) δ(ppm): 6.80 (d, J = ++++ ++ ++ diazabicyclo[3.2.1]octan-3-yl)-6- 12.9 Hz, 1H), 6.43 (d, J = 7.5 Hz, 1H), fluorochroman-3-yl)-6-amino-2- 4.62-4.59 (m, 1H), 4.44-4.35 (m, 1H), methylthieno[2,3-d]thiazole-5- 4.23-4.19 (m, 1H), 3.92-3.85 (m, 2H), carboxamide 3.31-3.29 (m, 2H), 3.08-2.78 (m, 7H), 2.17-2.15 (m, 2H), 2.09-1.91 (m, 2H). 47 N-((3R)-7-(3,8- 474 (MeOH-d4, 300 MHz) δ(ppm): 6.75 (d, J = ++ + + diazabicyclo[3.2.1]octan-3-yl)-6- 13.2 Hz, 1H), 6.36 (d, J = 7.5 Hz, 1H), fluorochroman-3-yl)-6-amino-2- 4.41-4.34 (m 1H) 4.21-4.17 (m, 1H) methylthieno[2,3-d]thiazole-5- 3.90-3.84 (m, 1H), 3.54-3.51 (m, 2H), carboxamide 3.20-3.15 (m, 2H), 2.99-2.84 (m, 7H), 2.01-1.97 (m, 2H), 1.91-1.84 (m, 2H). 48 (R)-3-amino-N-(5-chloro-7- 458, (DMSO-d6, 300 MHz) δ(ppm): 8.33 (d, J = ++++ +++ +++ (piperazin-1-yl)chroman-3-yl)-6- 460 8.4 Hz, 1H). 7.60 (br s, 1H), 7.31 (d, J = methylthieno[2,3-b]pyridine-2- 8.4 Hz 1H), 7.22 (br s, 2H), 6.64 (s carboxamide 1H), 6.33 (s, 1H), 4.36-4.27 (m, 1H), 4.17-4.14 (m, 1H), 3.85-3.79 (m, 1H), 3.08-3.01 (m, 5H), 2.97-2.74 (m, 6H), 2.58 (s, 3H). 49 (S)-3-amino-N-(5-chloro-7- 458, (DMSO-d6, 300 MHz) δ(ppm): 8.33 (d, J = ++ + + (piperazin-1-yl)chroman-3-yl)-6- 460 8.7 Hz, 1H). 7.60 (br s, 1H), 7.31 (d, J = methylthieno[2,3-b]pyridine-2- 8.7 Hz, 1H), 7.23 (br s, 2H), 6.64 (s, carboxamide 1H), 6.34 (s, 1H), 4.36-4.27 (m, 1H), 4.17-4.14 (m, 1H), 3.85-3.79 (m, 1H), 3.08-3.01 (m, 5H), 2.97-2.74 (m, 6H), 2.58 (s, 3H). 50 N-((3R)-7-(3,8- 420 (DMSO-d6, 400 MHz) δ(ppm): 8.31 (s, +++ ++ ++ diazabicyclo[3.2.1]octan-3- 1H), 7.96 (br s, 1H), 7.62 (s, 1H), 7.06 yl)chroman-3-yl)-5,6,7,8- (s, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.37 (d, tetrahydro-1,8-naphthyridine-3- J = 8.0 Hz, 1H), 6.16 (s, 1H), 4.23-4.21 carboxamide (m, 1H), 4.14-4.11 (m, 1H), 3.74 (t, J = 9.6 Hz, 1H), 3.45-3.32 (m, 2H), 3.33- 3.31 (m, 4H), 2.87-2.73 (m, 2H), 2.67- 2.65 (m, 4H), 2.42-2.28 (br s, 1H), 1.78- 1.77 (m, 2H), 1.65-1.63 (m, 4H). 51 N-((3R)-7-(3,8- 421 (DMSO-d6, 300 MHz) δ(ppm): 8.48 (s, ++ + + diazabicyclo[3.2.1]octan-3- 1H), 8.33 (br s, 1H), 7.98 (s, 1H), 6.89 yl)chroman-3-yl)-3,4-dihydro- (d, J = 8.4 Hz, 1H), 6.39 (dd, J = 2.1, 8.4 2H-pyrano[2,3-b]pyridine-6- Hz, 1H), 6.18 (s, 1H), 4.34-4.13 (m, 4H), carboxamide 3.83-3.78 (m, 1H), 3.48-3.46 (m, 2H), 3.32-3.29 (m, 2H), 2.94-2.74 (m, 5H), 2.69-2.66 (m, 2H), 1.97-1.90 (m, 2H), 1.67-1.65 (m, 4H). 52 (R)-6-(benzylamino)-N-(7- 444 (DMSO-d6, 300 MHz) δ(ppm): 8.50 (s, ++ + ++ (piperazin-1-yl)chroman-3- 1H), 8.04 (d, J = 6.9 Hz, 1H), 7.82 (dd, J = yl)nicotinamide 2.4, 9.0 Hz, 1H), 7.61 (br s, 1H), 7.32- 7.20 (m, 5H), 6.91(d, J = 8.4 Hz, 1H), 6.53-6.47 (m, 2H), 6.28 (s, 1H), 4.52 (m, 2H), 4.23-4.12 (m, 2H), 3.79-3.72 (m, 1H), 2.97-2.73 (m, 10H). 53 6-(((S)-1-phenylethyl)amino)-N- 458 (DMSO-d6, 300 MHz) δ(ppm): 8.45 (s, + + + ((R)-7-(piperazin-1-yl)chroman- 1H), 8.00 (br s, 1H), 7.79-7.76 (m, 1H), 3-yl)nicotinamide 7.55(d, J = 8.4 Hz, 1H), 7.37-7.18 (m 5H), 6.90 (d, J = 8.4 Hz, 1H), 6.47 (d, J = 8.7 Hz, 2H), 6.27 (s, 1H), 5.17-5.03 (m, 1H), 4.28-4.11 (m, 2H), 3.77-3.74 (m, 1H), 2.97-2.73 (m, 10H), 1.43(d, J = 7.2 Hz, 3H). 54 6-(((R)-1-phenylethyl)amino)-N- 458 (DMSO-d6, 300 MHz) δ(ppm): 8.44 (s, + + + ((R)-7-(piperazin-1-yl)chroman- 1H), 8.00 (br s, 1H), 7.80-7.76 (m, 1H), 3-yl)nicotinamide 7.56 (d, J = 7.8 Hz, 1H), 7.37-7.18 (m 5H), 6.90 (d, J = 8.7 Hz, 1H), 6.49-6.46 (m, 2H), 6.27 (s, 1H), 5.15-5.01 (m, 1H), 4.14-4.10 (m, 2H), 3.76-3.69 (m, 1H), 2.84-2.74 (m, 10H), 1.44 (d, J = 6.9 Hz, 3H). 55 (R)-3-amino-N-(5,8-difluoro-7- 460 (DMSO-d6, 400 MHz) δ(ppm): 8.33 (d, ++++ ++++ +++ (piperazin-1-yl)chroman-3-yl)-6- J = 8.0 Hz, 1H), 7.66 (br s, 1H), 7.31 (d, methylthieno[2,3-b]pyridine-2- J = 8.4 Hz, 1H), 7.24 (br s, 2H), 6.49- carboxamide 6.38 (m, 1H), 4.43-4.09 (m, 2H), 3.97- 3.95 (m, 1H), 3.01-2.69 (m, 10H), 2.58 (s, 3H). 56 (R)-6-amino-N-(5,8-difluoro-7- 466 (DMSO d6 300 MHz) δ(ppm): 7.58 (d, J = ++++ +++ ++ (piperazin-1-yl)chroman-3-yl)-2- 6.8 Hz, 1H), 7.16 (s, 2H), 6.46-6.42 methylthieno[2,3-d]thiazole-5- (m, 1H), 4.30-4.24 (m, 2H), 3.92 (m, carboxamide 1H), 3.32-2.33 (m, 10H), 2.08 (s, 3H). 57 (R)-7-hydroxy-N-((R)-7- 395 (DMSO-d6, 300 MHz) δ(ppm): 8.84 (s, + + + (piperazin-1-yl)chroman-3-yl)- 1H), 8.56 (br s, 1H), 8.05 (s, 1H), 6.94 6,7-dihydro-5H- (d, J = 8.4 Hz, 1H), 6.52 (dd, J = 2.4, 8.4 cyclopenta[b]pyridine-3- Hz 1H), 6.32 (s 1H), 5.50 (d, J = 5.6 Hz, carboxamide 1H), 4.98-4.96 (m, 1H), 4.29-4.27 (m, 1H), 4.20-4.17 (m, 1H), 3.86-3.83 (m, 1H), 3.03-2.75 (m, 12H), 2.49-2.33 (m, 2H), 1.86-1.84 (m, 1H). 58 (S)-7-hydroxy-N-((R )-7- 395 (DMSO d6, 300 MHz) δ(ppm): 8.84 (s, ++ + + (piperazin-1-yl)chroman-3-yl)- 1H), 8.55 (br s, 1H), 8.05 (s, 1H), 6.94 6,7-dihydro-5H- (d, J = 8.4 Hz, 1H), 6.52 (dd, J = 2.4, 8.4 cyclopenta[b]pyridine-3- Hz, 1H), 6.32 (s, 1H), 5.50 (d, J = 5.6 Hz carboxamide 1H), 4.98-4.96 (m, 1H), 4.29-4.27 (m, 1H), 4.20-4.17 (m, 1H), 3.86-3.83 (m, 1H), 3.03-2.75 (m, 12H), 2.49-2.33 (m, 2H), 1.86-1.84 (m, 1H). 59 (R)-1-benzyl-N-(7-(piperazin-1- 468 (DMSO-d6, 300 MHz) δ(ppm): 8.76 (s, ++++ +++ ++++ yl)chroman-3-yl)-1H-pyrrolo[2,3- 1H), 8.52-8.40 (m, 2H), 7.72 (d, J = 3.6 b]pyridine-5-carboxamide Hz, 1H), 7.33-7.22 (m, 5H), 6.93 (d, J = 8.4 Hz, 1H), 6.64 (d, J = 3.6 Hz, 1H), 6.51 (dd, J = 2.4, 8.4 Hz, 1H), 6.30 (s, 1H), 5.52 (s, 2H), 4.40-4.25 (m, 1H), 4.24-4.15 (m, 1H), 3.84 (t, J = 9.6 Hz, 1H), 2.98-2.87 (m, 5H), 2.84-2.73 (m, 5H). 60 (R)-7-amino-N-(8-cyano-5- 468 (DMSO-d6, 300 MHz) δ(ppm): 8.66 (s, +++ ++ ++ fluoro-7-(piperazin-1- 1H), 7.96 (br s, 1H), 7.01 (br s, 2H), yl)chroman-3-yl)-3- 6.56 (d, J = 9.3 Hz, 1H), 4.39-4.35 (m , methylthieno[2,3-b]pyrazine-6- 2H), 4.17-4.09 (m, 1H), 3.06-2.92 (m, carboxamide 5H), 2.83-2.74 (m, 5H), 2.65 (s, 3H), 2.27 (br s, 1H). 61 (R)-3-amino-N-(5,6-difluoro-7- 460 (DMSO-d6, 400 MHz) δ(ppm): 8.33 (d, J = ++++ +++ +++ (piperazin-1-yl)chroman-3-yl)-6- 8.4 Hz, 1H), 7.62 (br s, 1H), 7.31 (d, J = methylthieno[2,3-b]pyridine-2- 8.4 Hz, 1H), 7.23 (br s, 2H), 6.27 (d, J = carboxamide 5.6 Hz, 1H), 4.34-4.27 (m, 1H), 4.18- 4.14 (m, 1H), 3.88 (t, J = 10.0 Hz, 1H), 2.93-2.81 (m, 10H), 2.58 (s, 3H), 2.41 (br s, 1H). 62 3-amino-N-((R)-7-((3S,4R)-3- 439 (DMSO-d6, 400 MHz) δ(ppm): 8.32 (d, J = ++++ ++++ ++++ hydroxypiperidin-4-yl)chroman- 8.4 Hz, 1H). 7.56 (br s, 1H), 7.31 (d, J = 3-yl)-6-methylthieno[2,3- 8.0 Hz, 1H), 7.22 (br s, 2H), 6.98 (d, J = b]pyridine-2-carboxamide 7.6 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 6.70 (s, 1H), 4.36-4.30 (m, 1H), 4.29- 4.24 (m, 1H), 4.22-4.16 (m, 1H), 3.82 (t, J = 10.0 Hz, 1H), 3.62-3.58 (m, 1H), 3.02-2.85 (m, 4H), 2.74-2.55 (m, 7H), 2.01-1.89 (m, 1H), 1.38-1.34 (m, 1H). 63 3-amino-N-((R)-7-((3R,4S)-3- 439 (DMSO-d6, 400 MHz) δ(ppm): 8.32 (d, J = ++++ +++ +++ hydroxypiperidin-4-yl)chroman- 8.0 Hz, 1H). 7.55 (br s, 1H), 7.31 (d, J = 3-yl)-6-methylthieno[2,3- 8.0 Hz, 1H), 7.22 (br s, 2H), 6.98 (d, J = b]pyridine-2-carboxamide 7.6 Hz, 1H), 6.77 (d, J = 7.6 Hz, 1H), 6.70 (s, 1H), 4.36-4.30 (m, 1H), 4.29- 4.24 (m, 1H), 4.22-4.16 (m, 1H), 3.82 (t, J = 10.0 Hz, 1H), 3.62-3.58 (m, 1H), 3.02-2.85 (m, 4H), 2.74-2.55 (m, 7H), 2.02-1.88 (m, 1H), 1.38-1.35 (m, 1H). 64 3-amino-N-((R)-7-((3R,4R)-3- 439 (DMSO-d6, 400 MHz) δ(ppm): 8.32 (d, J = ++++ +++ hydroxypiperidin-4-yl)chroman- 8.4 Hz, 1H). 7.57 (br s, 1H), 7.31 (d, J = 3-yl)-6-methylthieno[2,3- 8.0 Hz, 1H), 7.22 (br s, 2H), 6.99 (d, J b]pyridine-2-carboxamide 8.0 Hz, 1H), 6,74 (d, J = 7.6 Hz, 1H), 6.64 (s, 1H), 4.37-4.28 (m, 1H), 4.19- 4.17 (m, 1H), 3.82 (t, J = 10.0 Hz, 1H), 3.43-3.37 (m, 1H), 3.05-2.84 (m, 4H), 2.58 (s, 3H), 2.50-2.21 (m, 4H), 1.65- 1.60 (m, 1H), 1.53-1.42 (m, 1H). 65 3-amino-N-((R)-7-((3S,4S)-3- 439 (DMSO-d6, 400 MHz) δ(ppm): 8.32 (d, J = ++++ +++ hydroxypiperidin-4-yl)chroman- 8.4 Hz, 1H). 7.56 (br s, 1H), 7.31 (d, J = 3-yl)-6-methylthieno[2,3- 8.4 Hz, 1H), 7.22 (br s, 2H), 6.99 (d, J = b]pyridine-2-carboxamide 7.6 Hz, 1H), 6.74 (d, J = 76. Hz, 1H), 6.64 (s, 1H), 4.35-4.29 (m, 1H), 4.19- 4.17 (m, 1H), 3.82 (t, J = 10.0 Hz, 1H), 3.43-3.37 (m, 1H), 3.05-2.84 (m, 4H), 2.58 (s, 3H), 2.50-2.21 (m, 4H), 1.65- 1.60 (m, 1H), 1.53-1.42 (m, 1H). 66 (R)-6-amino-N-(5,6-difluoro-7- 466 (DMSO-d6, 300 MHz) δ(ppm): 7.53 (d, J = ++++ ++ (piperazin-1-yl)chroman-3-yl)-2- 6.9 Hz, 1H), 7.15 (s, 2H), 6.27-6.24 methylthieno[2,3-d]thiazole-5- (m, 1H), 4.27-4.15 (m, 1H), 4.13-4.12 carboxamide (m, 1H), 3.89-3.82 (m, 1H), 2.96-2.87 (m, 5H), 2.82-2.73 (m, 8H). 67 (R)-7-amino-N-(6-cyano-5- 468 (DMSO-d6, 300 MHz) δ(ppm): 8.66 (s, ++++ +++ fluoro-7-(piperazin-1- 1H), 7.91 (br s, 1H), 7.01 (br s, 2H), yl)chroman-3-yl)-3- 6.37 (s, 1H), 4.31-4.27 (m, 2H), 4.10- methylthieno[2,3-b]pyrazine-6- 4.07 (m, 1H), 3.05-3.02 (m, 5H), 2.85- carboxamide 2.83 (m, 5H), 2.65 (s, 3H). 68 (R)-3-amino-N-(5,8-difluoro-7- 444 (MeOH-d4, 300 MHz) δ(ppm): 8.12 (d, J = ++ + (piperazin-1-yl)chroman-3-yl)-6- 8.7 Hz, 1H), 7.21 (d, J = 8.7 Hz, 1H), methylfuro[2,3-b]pyridine-2- 6.45-6.32 (m, 1H), 4.63-4.40 (m, 1H), carboxamide 3.38-3.29 (m, 1H), 4.12-3.96 (m, 1H), 3.15-2.94 (m, 9H), 2.90-2.78 (m, 1H), 2.61 (s, 3H). 69 3-amino-N-((R)-7-((R)-3,3- 459 (DMSO-d6, 300 MHz) δ(ppm): 8.32 (d, J = ++++ +++ difluoropiperidin-4-yl)chroman- 8.1 Hz, 1H), 7.60 (br s, 1H), 7.31 (d, J = 3-yl)-6-methylthieno[2,3- 8.4 Hz, 1H), 7.23 (br s, 2H), 7.03 (d, J = b]pyridine-2-carboxamide 6.8 Hz, 1H) 6.80 (d, J = 8.1 Hz, 1H), 6.72 (s, 1H), 4.33-4.25 (m, 1H), 4.21- 4.14 (m, 1H), 3.85 (t, J = 9.9 Hz, 1H), 3.13-3.02 (m, 2H), 3.02-2.92 (m, 4H), 2.91-2.74 (m, 1H), 2.62-2.60 (m, 1H), 2.58 (s, 3H), 2.49 (br s, 1H), 1.93-1.74 (m, 1H), 1.75-1.69 (m, 1H). 70 3-amino-N-((R)-7-((S)-3,3- 459 (DMSO-d6, 300 MHz) δ(ppm): 8.33 (d, J = ++++ ++++ difluoropiperidin-4-yl)chroman- 8.1 Hz, 1H), 7.60 (br s, 1H), 7.32 (d, J = 3-yl)-6-methylthieno[2,3- 8.4 Hz, 1H), 7.23 (br s, 2H), 7.03 (d, J = b]pyridine-2-carboxamide 6.8 Hz, 1H) 6.80 (d, J = 7.5 Hz, 1H), 6.72 (s, 1H), 4.32-4.25 (m, 1H), 4.21- 4.17 (m, 1H), 3.85 (t, J = 9.9 Hz, 1H), 3.13-3.02 (m, 2H), 3.02-2.92 (m, 4H), 2.91-2.73 (m, 1H), 2.62-2.60 (m, 1H), 2.58 (s, 3H), 2.49 (br s, 1H), 1.94-1.74 (m, 1H), 1.74-1.69 (m, 1H). 71 (R)-7-amino-3-methyl-N-(7- 426 (DMSO-d6, 300 MHz) δ(ppm): 8.65 (s, +++ ++ (piperazin-1-yl)-3,4-dihydro-2H- 1H), 7.84-7.82 (m, 2H), 6.99 (br s, 2H), pyrano[3,2-c]pyridin-3- 6.14 (s, 1H), 4.29-4.21 (m, 2H), 3.94- yl)thieno[2,3-b]pyrazine-6- 3.88 (m, 1H), 3.32-3.27 (m, 4H), 2.85- carboxamide 2.82 (m, 2H), 2.76-2.70 (m, 4H), 2.65 (s, 3H). 72 (R)-3-amino-5-fluoro-6-methyl- 443 (DMSO-d6, 300 MHz) δ(ppm): 8.31 (d, J = ++++ ++ N-(7-(piperazin-1-yl)-3,4- 10.2 Hz, 1H), 7.83 (s, 1H), 7.67 (br s, dihydro-2H-pyrano[3,2- 1H), 7.19 (br s, 2H), 6.14 (s, 1H), 4.30- c]pyridin-3-yl)thieno[2,3- 4.19 (m, 2H), 3.93-3.86 (m, 1H), 3.31- b]pyridine-2-carboxamide 3.27 (m, 4H), 2.84-2.81 (m, 2H), 2.79- 2.73 (, 4H), 2.56-2.51 (s, 3H). 73 (7S)-N-((3R)-7-(3,8- 434 (DMSO-d6, 400 MHz) δ(ppm): 8.33 (s, + + diazabicyclo[3.2.1]octan-3- 1H), 7.98 (br s, 1H), 7.63 (s, 1H), 7.08 yl)chroman-3-yl)-7-methyl- (s, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.38- 5,6,7,8-tetrahydro-1,8- 6.35 (m, 1H), 6.16 (s, 1H), 4.25-4.18 (m, naphthyridine-3-carboxamide 1H), 4.13-4.10 (m, 1H), 3.76-3.71 (m , 1H), 3.47 (s, 3H), 3.34-3.28 (m, 2H) 2.87-2.73 (m, 2H), 2.69-2.65 (m, 4H), 1.88-1.84 (m, 1H), 1.66-1.64 (m, 4H), 1.45-1.36 (m, 1H), 1.17 (d, J = 6.4 Hz, 3H). 74 (7R)-N-((3R)-7-(3,8- 434 (DMSO-d6, 400 MHz) δ(ppm): 8.33 (s, +++ ++ diazabicyclo[3.2.1]octan-3- 1H), 7.98 (br s, 1H), 7.63 (s, 1H), 7.08 yl)chroman-3-yl)-7-methyl- (s, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.38- 5,6,7,8-tetrahydro-1,8- 6.35 (m, 1H), 6.16 (s, 1H), 4.27-4.18 (m, naphthyridine-3-carboxamide 1H), 4.13-4.10 (m, 1H), 3.76-3.71 (m, 1H), 3.47 (s, 3H), 3.34-3.22 (m, 2H) 2.87-2.73 (m, 2H), 2.68-2.65 (m, 4H), 1.89-1.84 (m, 1H), 1.66-1.64 (m, 4H), 1.45-1.36 (m, 1H), 1.17 (d, J = 6.4 Hz, 3H). 75 N-((R)-7-((1S, 4S)-2 5- 451 (DMSO-d6, 300 MHz) δ(ppm): 8.33 (d, J = ++++ ++++ diazabicyclo[2.2.2]octan-2-yl)- 8.1 Hz, 1H), 7.76 (s, 1H), 7.58 (br s, 3,4-dihydro-2H-pyrano[3,2- 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.23 (s, c]pyridin-3-yl)-3-amino-6- 1H), 5.81 (s, 1H), 4.50-4.49 (m, 1H), methylthieno[2,3-b]pyridine-2- 4.27-4.19 (m, 2H), 3.88 (t, J = 9.9 Hz, carboxamide 1H), 3.46-3.35 (m, 1H), 3.33-3.28 (m, 1H), 3.19-2.91 (m, 3H), 2.88-2.74 (m, 2H), 2.58 (s, 3H), 1.94-1.72 (m, 3H), 1.72-1.59 (m, 1H). 76 N-((R)-7-((1 R,4R)-2,5- 451 (DMSO-d6, 300 MHz) δ(ppm): 8.32 (d, J = ++++ +++ diazabicyclo[2.2.2]octan-2-yl)- 8.1 Hz, 1H), 7.76 (s, 1H), 7.58 (br s, 3,4-dihydro-2H-pyrano[3,2- 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.23 (s, c]pyridin-3-yl)-3-amino-6- 1H), 5.81 (s, 1H), 4.50-4.49 (m, 1H), methylthieno[2,3-b]pyridine-2- 4.27-4.18 (m, 2H), 3.88 (t, J = 9.9 Hz, carboxamide 1H), 3.46-3.34 (m, 1H), 3.33-3.27 (m, 1H), 3.19-2.91 (m, 3H), 2.88-2.74 (m, 2H), 2.58 (s, 3H), 1.94-1.72 (m, 3H), 1.72-1.58 (m, 1H). 77 N-((3R)-7-(3,6- 480 (MeOH-d4, 300 MHz) δ(ppm): 8.57 (s, +++ ++ diazabicyclo[3.1.1]heptan-3-yl)- 1H), 6.29 (s, 1H), 4.52-4.45 (m, 1H), 8-cyano-5-fluorochroman-3-yl)- 4.40-4.37 (m, 1H), 4.18-4.16 (m, 1H), 7-amino-3-methylthieno[2,3- 3.95-3.92 (m, 2H), 3.84-3.79 (m, 4H), b]pyrazine-6-carboxamide 3.13-2.96 (m, 1H), 2.78-2.70 (m, 2H), 2.68 (s, 3H), 1.70 (d, J = 9.2 Hz, 1H). 78 N-((3R)-7-(9-oxa-3,7- 502 (DMSO-d6, 300 MHz) δ(ppm): 8.33 (d, J = ++++ ++++ diazabicyclo[3.3.1]nonan-3-yl)- 8.4 Hz, 1H). 7.67 (br s, 1H), 7.31 (d, J = 5,8-difluorochroman-3-yl)-3- 8.1 Hz, 1H), 7.24 (br s, 2H), 6.52-6.46 amino-6-methylthieno[2,3- (m, 1H), 4.33-4.27 (m, 2H), 4.00-3.94 b]pyridine-2-carboxamide (m, 1H), 3.67-3.65 (m, 2H), 3.42-3.36 (m, 3H), 3.23-3.10 (m, 4H), 2.99-2.79 (m, 4H), 2.58 (s, 3H). 79 N-((3R)-7-(9-oxa-3,7- 502 (DMSO-d6, 300 MHz) δ(ppm): 8.33 (d, J = ++++ ++++ diazabicyclo[3.3.1]nonan-3-yl)- 8.4 Hz, 1H). 7.62 (br s, 1H), 7.31 (d, J = 5,6-difluorochroman-3-yl)-3- 8.4 Hz, 1H), 7.24 (br s, 2H), 6.31-6.28 amino-6-methylthieno[2,3- (m, 1H), 4.33-4.28 (m, 1H), 4.20-4.15 b]pyridine-2-carboxamide (m, 1H), 3.93-3.87 (m, 1H), 3.66-3.65 (m, 2H), 3.42-3.36 (m, 3H), 3.20-3.09 (m, 4H), 2.98-2.73 (m, 4H), 2.58 (s, 3H). 80 3-amino-N-((R)-7-((3R,4R)-3- 441 (DMSO-d6, 400 MHz) δ(ppm): 8.33 (d, J = ++++ +++ fluoropiperidin-4-yl)chroman-3- 8.4 Hz, 1H), 7.58 (br s, 1H), 7.31 (d, J = yl)-6-methylthieno[2,3- 8.4 Hz, 1H), 7.23 (br s, 2H), 7.05 (d b]pyridine-2-carboxamide J = 12.0 Hz, 1H), 6.80 (d, J = 80 Hz, 1H), 6.70 (s, 1H), 4.70-4.57 (m, 1H), 4.33-4.29 (m, 1H), 4.20-4.17 (m, 1H), 3.84 (t, J = 10.0 Hz, 1H), 3.32-2.62 (m, 7H), 2.58 (s, 3H), 1.93-1.88 (m, 1H), 1.56-1.52 (m, 1H). 81 3-amino-N-((R)-7-((3S,4S)-3- 441 (DMSO-d6, 400 MHz) δ(ppm): 8.33 (d, J = ++++ +++ fluoropiperidin-4-yl)chroman-3- 8.4 Hz, 1H), 7.58 (br s, 1H), 7.31 (d, J = yl)-6-methylthieno[2,3- 8.4 Hz, 1H), 7.22 (br s, 2H), 7.04 (d, b]pyridine-2-carboxamide J = 8.0 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 6.71 (s, 1H), 4.70-4.57 (m, 1H), 4.33- 4.29 (m, 1H), 4.20-4.17(m, 1H), 3.84 (t, J = 10.0 Hz, 1H), 3.32-2.61 (m, 7H), 2.58 (s, 3H), 1.93-1.88 (m, 1H), 1.56- 1.52 (m, 1H). 82 3-amino-N-((R)-7-((3S,4R)-3- 441 DMSO-d6, 400 MHz) δ(ppm): 8.33 (d, J = ++++ ++++ fluoropiperidin-4-yl)chroman-3- 8.0 Hz, 1H), 7.59 (br s, 1H), 7.31 (d, J = yl)-6-methylthieno[2,3- 8.0 Hz, 1H), 7.23 (br s, 2H), 7.05 (d, b]pyridine-2-carboxamide J = 7.6 Hz, 1H), 6.81-6.79 (m, 1H), 6.71 (s, 1H), 4.60-4.57 (m, 1H), 4.34-4.30 (m, 1H), 4.20-4.17 (m, 1H), 3.84 (t, J = 10.0 Hz, 1H), 3.27-3.24 (m, H), 2.98-2.86 (m, 3H), 2.69-2.61 (m, 1H), 2.58 (s, 3H), 2.50-2.43 (m, 2H), 1.74-1.71 (m, 1H), 1.61-1.54 (m 1H). 83 3-amino-N-((R)-7-((3R,4S)-3- 441 (DMSO-d6, 400 MHz) δ(ppm): 8.33 (d, J = ++++ +++ fluoropiperidin-4-yl)chroman-3- 8.4 Hz, 1H), 7.59 (br s, 1H), 7.32 (d, J = yl)-6-methylthieno[2,3- 8.4 Hz, 1H), 7.23 (br s, 2H), 7.05 (d, b]pyridine-2-carboxamide J = 7.6 Hz, 1H), 6.81-6.79 (m, 1H), 6.72 (s 1H), 4.60-4.57 (m, 1H), 4.34-4.30 (m, 1H), 4.20-4.17 (m, 1H), 3.84 (t, J = 10.0 Hz, 1H), 3.27-3.24 (m, H), 2.98-2.86 (m, 3H), 2.69-2.61 (m, 1H), 2.58 (s, 3H), 2.50-2.43 (m, 2H), 1.74-1.71 (m, 1H), 1.61-1.54 (m, 1H). 84 N-((R)-5,8-difluoro-7-((3R,4S)- 458 (DMSO-d6, 300 MHz) δ(ppm): 9.06 (d, J = ++ + 3-hydroxypiperidin-4- 7.8 Hz, 1H), 8.47 (s, 1H), 8.10 (br s, yl)chroman-3-yl)-7-ethyl-7H- 1H), 6.76-6.71 (m, 2H), 4.66 (br s, 1H), pyrrolo[2,3-c]pyridazine-3- 4.58-4.42 (m, 3H), 4.47-4.30 (m, 1H), carboxamide 4.22-4.16 (m, 1H), 3.68-3.67 (m, 1H), 3.20-3.00 (m, 4H), 3.00-2.80 (m, 2H), 2.78-2.58 (m, 1H), 2.06-1.97 (m, 1H), 1.47 (t, J = 7.2 Hz, 3H), 1.40-1.30 (m, 1H), 1.38-1.35 (m, 1H). 85 N-((R)-5,8-difluoro-7-((3S,4R)- 458 (DMSO-d6, 300 MHz) δ(ppm): 9.08 (d, J = ++ + 3-hydroxypiperidin-4- 7.5 Hz, 1H), 8.47 (s, 1H), 8.10 (br s, yl)chroman-3-yl)-7-ethyl-7H- 1H), 6.76-6.70 (m, 2H), 5.31 (br s, 1H), pyrrolo[2,3-c]pyridazine-3- 4.55-4.47 (m, 3H), 4.35-4.33 (m, 1H), carboxamide 4.23-4.17 (m, 1H), 3.90-3.89 (m, 1H), 3.22-3.17 (m, 2H), 3.15-2.91 (m, 5H), 2.26-2.18 (m, 1H), 1.56-1.55 (m, 1H), 1.47 (t, J = 7.2 Hz, 3H), 1.28-1.24 (m, 1H). 86 3-amino-N-((R-7-((3R,4R-3- 490 (DMSO-d6, 400 MHz) δ(ppm): 8.32 (d, J = ++++ ++ amino-4-methoxypyrrolidin-1- 8.4 Hz, 1H), 7.63 (br s, 1H), 7.32 (d, J = yl)-5,8-difluorochroman-3-yl)-6- 8.4 Hz, 1H), 7.23 (br s, 2H), 6.15 (dd, methylthieno[2,3-b]pyridine-2- J = 2.4, 12.4 Hz, 1H), 4.30-4.24 (m, 2H), carboxamide 3.95-3.90 (m, 1H), 3.67-3.61 (m, 2H), 3.52-3.50 (m, 1H), 3.41-3.40 (m, 1H), 3.29 (s, 3H), 3.25-3.22 (m, 1H), 3.05- 3.02 (m, 1H), 2.89-2.80 (m, 1H), 2.78- 2.74 (m, 1H), 2.59 (s, 3H), 2.48-2.18 (br s, 2H). 87 3-amino-N-((R)-7-((3S,4S)-3- 490 (DMSO-d6, 400 MHz) δ(ppm): 8.32 (d, J = ++++ ++ amino-4-methoxypyrrolidin-1- 8.4 Hz, 1H), 7.62 (br s, 1H), 7.32 (d, J = yl)-5,8-difluorochroman-3-yl)-6- 8.4 Hz, 1H), 7.24 (br s, 2H), 6.15 (dd, methylthieno[2,3-b]pyridine-2- J = 2.4, 12.4 Hz, 1H), 4.30-4.24 (m, 2H), carboxamide 3.95-3.90 (m, 1H), 3.67-3.61 (m, 2H), 3.52-3.50 (m, 1H), 3.41-3.40 (m, 1H) 3.29 (s, 3H), 3.25-3.22 (m, 1H), 3.05- 3.02 (m, 1H), 2.89-2.80 (m, 1H), 2.78- 2.74 (m, 1H), 2.59 (s, 3H), 2.48-2.18 (br s, 2H). 88 N-((3R)-7-(9-oxa-3,7- 516 (DMSO-d6, 400 MHz) δ(ppm): 7.83 (br ++++ ++++ diazabicyclo[3.3.1]nonan-3- s, 1H), 7.80-7.56 (m, 1H), 7.55 (s, 1H), yl)chroman-3-yl)-3-amino-4- 6.97 (d, J = 8.4 Hz, 1H), 6.76 (br s, 2H), (difluoromethyl)-6- 6.58 (d, J = 8.8 Hz, 1H), 6.37 (s, 1H), methylthieno[2,3-b]pyridine-2- 4.38-4.25 (m, 1H), 4.20-4.12 (m, 1H), carboxamide 3.85-3.80 (m, 1H), 3.74-3.60 (m, 4H), 3.12-3.03 (m, 2H), 3.01-2.91(m, 4H), 2.90-2.85 (m, 2H), 2.65 (s, 1H). 89 (1aS, 7bR)-N-((3R)-7-(3 8- 468 (DMSO-d6, 400 MHz) δ(ppm): 8.29 (s, ++++ +++ diazabicyclo[3.2.1]octan-3-yl)- 1H), 8.17 (br s, 1H), 7.86 (s, 1H), 6.63 5,8-difluorochroman-3-yl)- (s, 1H), 6.36-6.30 (m, 1H), 4.40-4.22 (m , 1a,2,3,7b-tetrahydro-1H- 2H), 3.98-3.90 (m, 1H), 3.60-3.49 (m, cyclopropa[c][1,8]naphthyridine- 4H), 3.11-3.07 (m, 2H), 3.00-2.72 (m, 6-carboxamide 4H), 2.00-1.60 (m, 6H), 0.96-0.94 (m, 2H). 90 (1aR,7bS)-N-((3R)-7-(3,8- 468 (DMSO-d6, 400 MHz) δ(ppm): 8.26 (s, ++ ++ diazabicyclo[3.2.1]octan-3-yl)- 1H), 8.18-8.16 (m, 1H), 7.86 (s, 1H), 5,8-difluorochroman-3-yl)- 6.63 (s, 1H), 6.40-6.30 (m, 1H), 4.40- 1a,2,3,7b-tetrahydro-1H- 4.22 (m, 2H), 3.98-3.90 (m, 1H), 3.60- cyclopropa[c][1,8]naphthyridine- 2.72 (m, 4H), 2.00-1.60 (m, 6H), 0.96- 6-carboxamide 0.94 (m, 2H). 91 3-amino-N-[(3R )-7-[(3R,4R)-3- 472 (DMSO-d6, 400 MHz) δ(ppm): 8.33 (d, +++ ++ amino-4-methoxypyrrolidin-1- J = 8.3 Hz, 1H), 7.56 (br s, 1H), 7.31 (d, yl]-8-fluoro-3,4-dihydro-2H-1- J = 8.3 Hz, 1H), 7.23 (br s, 2H), 6.71 (d, benzopyran-3-yl]-6- J = 8.4 Hz, 1H), 6.28-6.21 (m, 1H), 4.36- methylthieno[2,3-b]pyridine-2- 4.20 (m, 2H),3.913.82 (m, 1H), 3.65- carboxamide 3.58 (m, 2H), 3.54-3.45 (m, 1H), 3.41- 3.34 (m, 1H), 3.28 (s, 3H), 3.20-3.18 (m, 1H), 3.02-2.95 (m, 1H), 2.89 (m, 2H), 2.58 (s, 3H), 2.05-1.95 (m, 2H). 92 3-amino-N-[(3R)-7-[(3S,4S)-3- 472 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, ++++ ++ amino-4-methoxypyrrolidin-1- J = 8.3 Hz, 1H), 7.58 (br s, 1H), 732 (d yl]-8-fluoro-3,4-dihydro-2H-1- J = 8.3 Hz, 1H), 7.24 (br s, 2H), 6.71 (d, benzopyran-3-yl]-6- J = 8.5 Hz, 1H), 6.25-6.21 (m, 1H), 4.37- methylthieno[2,3-b]pyridine-2- 4.20 (m, 2H), 3.86-3.81 (m, 1H), 3.67- carboxamide 3.56 (m, 2H), 3.58-3.41 (m, 3H), 3.42- 3.35 (m, 2H), 3.28-3.24 (m, 3H), 3.21- 3.18 (m, 1H), 3.05-2.95 (m,1H), 2.90- 2.85 (m, 2H), 2.60-2.55 (s, 3H),1.85-1.60 (s,2H). 93 3-amino-N-[(3R)-7-[(3R,4R)-3- 472 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, +++ ++ amino-4-methoxypyrrolidin-1- J = 8.0 Hz, 1H), 7.53 (br s, 1H), 7.31 (d, yl]-6-fluoro-3,4-dihydro-2H-1- J = 8.4 Hz, 1H), 7.22 (br s, 2H), 6.82 (d benzopyran-3-yl]-6- J = 14.0 Hz, 1H), 6.09 (d, J = 8.0 Hz, methylthieno[2,3-b]pyridine-2- 1H), 4.29-4.25 (m, 1H), 4.14-4.11 (m carboxamide 1H), 3.82-3.77 (m, 1H), 3.64-3.60 (m, 2H), 3.50-3.43 (m, 2H), 3.29 (s, 3H), 3.20-3.17 (m, 1H), 3.04-3.02 (m, 1H), 2.90-2.80 (m, 2H), 2.58 (s, 3H). 94 3-amino-N-[(3R)-7-[(3S,4S)-3- 472 (DMSO-d6, 400 MHz) δ (ppm): 8.32 (d, ++++ ++ amino-4-methoxypyrrolidin-1- J = 8.4 Hz, 1H), 7.53 (br s, 1H), 7.31 (d, yl]-6-fluoro-3,4-dihydro-2H-1- J = 8.0 Hz, 1H), 7.22 (br s, 2H), 6.82 (d benzopyran-3-yl]-6- J = 14.0 Hz, 1H), 6.08 (d, J = 8.0 Hz, methylthieno[2,3-b]pyridine-2- 1H), 4.29-4.25 (m, 1H), 4.14-4.11 (m, carboxamide 1H), 3.80-3.75 (m, 1H), 3.62-3.61 (m, 2H), 3.48-3.45 (m, 2H), 3.28 (s, 3H), 3.20-3.17 (m, 1H), 2.97-2.95 (m, 1H), 2.84-2.82 (m, 2H), 2.58 (s, 3H). 95 3-amino-N-[(3R)-8-cyano-7- 493 (DMSO-d6, 400 MHz) δ (ppm): 8.32 (d, ++++ ++ {3,8-diazabicyclo[3.2.1]octan-3- J = 8.4 Hz, 1H), 7.70(d, J = 6.8 Hz, 1H), yl}-5-fluoro-3,4-dihydro-2H-1- 7.31 (d, J = 8.4 Hz, 1H), 7.24 (br s, 2H), benzopyran-3-yl]-6- 6.47 (d, J = 12.0 Hz, 1H), 4.34-4.32 (m, methylthieno[2,3-b]pyridine-2- 2H), 4.09-4.08 (m, 1H), 3.43 (s, 2H), carboxamide 3.29-3.26 (m, 2H), 2.89-2.87 (m, 3H), 2.80-2.73 (m, 1H), 2.58 (s, 3H), 1.89- 1.86 (m, 2H), 1.65-1.63 (m, 2H). 96 3-amino-N-[(3R)-8-cyano-5- 509 (DMSO-d6, 400 MHz) δ (ppm): 8.34 (d, ++++ +++ fluoro-7-{9-oxa-3,7- J = 8.4 Hz, 1H), 7.74 (d, J = 6.8 Hz, 1H), diazabicyclo[3.3.1]nonan-3-yl}- 7.33 (d, J = 8.0 Hz, 1H), 7.27 (br s, 2H), 3,4-dihydro-2H-1-benzopyran-3- 6.65 (d, J = 11.6 Hz, 1H), 4.39-4.37 (m, yl]-6-methylthieno[2,3- 2H), 4.16-4.11 (m, 1H), 3.70 (s, 2H), b]pyridine-2-carboxamide 3.57-3.53 (m, 2H), 3.30-3.28 (m, 2H), 3.18-2.94 (m, 5H), 2.85-2.79 (m, 1H), 2.60 (s, 3H). 97 7-amino-N-[(3R)-7-{3,8- 487 (DMSO-d6, 400 MHz) δ (ppm): 8.65 (s, ++++ ++++ diazabicyclo[3.2.1]octan-3-yl]- 1H), 7.85 (d, J = 6.8 Hz, 1H), 6.99 (br s, 5,6-difluoro-3,4-dihydro-2H-1- 2H), 6.16 (d, J = 6.4 Hz, 1H), 4.33-4.29 benzopyran-3-yl]-3- (m, 1H), 4.17-4.14 (m, 1H), 3.92-3.87 methylthieno[2,3-b]pyrazine-6- (m, 1H), 3.42-3.35 (m, 2H), 3.09-3.06 carboxamide (m, 2H), 2.97-2.92 (m, 1H), 2.84-2.79 (m, 3H), 2.65 (s, 3H), 1.79-1.78 (m, 2H), 1.67-1.66(m, 2H). 98 6-amino-N-[(3R)-7-{3,8- 492 (DMSO-d6 300 MHz) δ (ppm): 7.57 (d, diazabicyclo[3.2.1]octan-3-yl}- J = 6.9 Hz, 1H), 7.17 (br s, 2H), 6.36- ++++ +++ 5,8-difluoro-3,4-dihydro-2H-1- 6.30 (m, 1H), 4.29-4.22(m, 2H), 3.95- benzopyran-3-yl]-2- 3.88 (m, 1H), 3.38-3.34 (m, 2H), 3.07- methylthieno[2,3-d][1, 3]thiazole- 3.04 (m, 2H), 2.95-2.87(m, 1H), 2.80- 5-carboxamide 2.72(m, 6H), 1.79-1.64 (m, 4H). 99 3-amino-N-[(2S)-5-fluoro-6-{9- 482 (DMSO-d6, 400 MHz) δ (ppm): 9.18 (s, ++++ ++++ oxa-3,7- 1H), 8.32-8.30 (m, 2H), 7.61 (d, J = 8.0 diazabicyclo[3.3.1]nonan-3-yl}- Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.19- 1,2,3,4-tetrahydronaphthalen-2- 7.12 (m, 1H), 6.95-6.89 (m, 2H), 4.15- yl]-6-methylthieno[2,3- 4.11 (m, 1H), 3.50-3.36 (m, 6H), 3.26- b]pyridine-2-carboxamide 3.18 (m, 2H), 2.99-2.94 (m, 2H), 2.86- 2.82 (m, 1H), 2.79-2.67 (m, 1H), 2.59 (s, 3H), 2.08-2.04 (m, 1H), 1.82-1.71 (m, 1H). 100 3-amino-N-[(2R)-5-fluoro-6-{9- 482 (DMSO-d6, 400 MHz) δ (ppm): 9.16 (s, +++ + oxa-3,7- Hz, 1H), 7.31 = 8.4 Hz, 1H), 7.23- diazabicyclo[3.3.1]nonan-3-yl}- 1H), 8.32-8.30 (m, 2H), 7.60 (d, J = 8.0 1,2,3,4-tetrahydronaphthalen-2- 7.10 (m, 1H), 6.97-6.89 (m, 2H), 4.16- yl]-6-methylthieno[2,3- 4.10 (m, 1H), 3.48-3.35 (m, 6H), 3.26- b]pyridine-2-carboxamide 3.18 (m, 2H), 2.99-2.95 (m, 2H), 2.86- 2.82 (m, 1H), 2.79-2.66 (m, 1H), 2.59 (s, 3H), 2.08-2.04 (m, 1H), 1.82-1.72 (m, 1H). 101 3-amino-N-[(2S)-7-fluoro-6-{9- 482 (DMSO-d6, 400 MHz) δ (ppm): 8.31 (d, ++++ ++ oxa-3,7- J = 8.0 Hz, 1H), 7.60 (d, J = 8.00 Hz, diazabicyclo[3.3.1]nonan-3-yl}- 1H), 7.31 (s, J = 8.00 Hz, 1H), 7.17 (br, 1,2,3,4-tetrahydronaphthalen-2- 1H), 6.93 (d, J = 16.6 Hz, 1H), 6.70 (d, J = yl]-6-methylthieno[2,3- 16.6 Hz, 1H), 4.13-4.09 (m, 1H), 3.70- b]pyridine-2-carboxamide 3.62 (m, 2H), 3.58-3.51(m, 1H), 3.23- 3.09 (m, 5H), 3.08-2.78 (m, 7H), 2.57 (s, 3H), 2.01-1.90 (m, 1H), 1.89-1.68 (m, 1H). 102 3-amino-N-[(2S)-5-cyano-6-{9- 489 (DMSO-d6 400 MHz) δ (ppm): 8.31 (d, ++++ +++ oxa-3,7- J = 8.0 Hz, 1H), 7.65 (d, J = 8.00 Hz, diazabicyclo[3.3.1]nonan-3-yl}- 1H), 7.39 (d, J = 8.8 Hz ) 7.31 (d, J = 1,2,3,4-tetrahydronaphthalen-2- 8.00 Hz, 1H), 7.18 (br s, 2H), 7.04 (d, J = yl]-6-methylthieno[2,3- 8.40 Hz, 1H), 4.19-4.09 (m, 1H), 3.70- b]pyridine-2-carboxamide 3.65 (m, 2H), 3.54-3.43 (m, 2H), 3.29- 3.20 (m, 2H), 3.08-2.70 (m, 9H), 2.58 (s, 3H), 2.09-1.99 (m, 1H), 1.89-1.70 (m, 1H). 103 3-amino-N-[(3R)-7-{3,8- 468 (DMSO-d6, 400 MHz) δ (ppm): 8.31 (d, ++++ +++ diazabicyclo[3.2.1]octan-3-yl}-8- J = 8.4 Hz, 1H), 7.62 (br s, 1H), 7.31 (d, fluoro-3,4-dihydro-2H-1- J = 8.4 Hz, 1H), 7.21 (br s, 2H), 6.78 (d, benzopyran-3-yl]-6- J = 8.0 Hz, 1H), 6.47-6.43 (m, 1H), 4.37- methylthieno[2,3-b]pyridine-2- 4.23 (m, 2H), 3.91-3.85 (m, 1H), 3.33- carboxamide 3.20 (m, 2H), 3.02-3.01 (m, 2H), 2.93- 2.91 (m, 2H), 2.81-2.79 (m, 2H), 2.58 (s, 3H), 1.81-1.79 (m, 2H), 1.69-1.63 (m, 2H). 104 3-amino-N-[(3R)-7-{3,8- 468 (DMSO-d6, 300 MHz) δ (ppm): 8.30 (d, ++++ ++++ diazabicyclo[3.2.1]octan-3-yl]-6- J = 6.0 Hz, 1H), 7.54 (br s, 1H), 7.31 (d, fluoro-3,4-dihydro-2H-1- J = 8.4 Hz, 1H), 7.22 (br s, 2H), 6.85 (d, benzopyran-3-yl]-6- J = 13.5 Hz, 1H), 6.29 (d, J = 7.8 Hz, methylthieno[2,3-b]pyridine-2- 1H), 4.27-4.23 (m, 1H), 4.15-4.11 (m, carboxamide 1H), 3.83-3.76 (m, 1H), 3.38-3.33 (m, 3H), 3.07-2.93 (m, 2H), 2.86-2.64 (m, 2H), 2.81-2.71 (m, 2H), 2.58 (s, 3H), 1.87-1.71 (m, 2H), 1.65-1.60 (m, 2H). 105 3-amino-N-[(3R)-8-fluoro-7-{9- 484 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, ++++ ++++ oxa-3,7- J = 8.4 Hz, 1H), 7.61 (br s, 1H), 7.31 (d, diazabicyclo[3.3.1]nonan-3-yl}- J = 8.4 Hz, 1H), 7.23 (br s, 2H), 6.87 (d, 3,4-dihydro-2H-1-benzopyran-3- J = 8.4 Hz, 1H), 6.60-6.55 (m, 1H), 4.37- yl]-6-methylthieno[2,3- 4.26 (m, 2H), 3.90-3.88 (m, 1H), 3.53- b]pyridine-2-carboxamide 3.51 (m, 2H), 3.32-3.10 (m, 6H), 2.99- 2.95 (m, 4H), 2.55 (s, 3H). 106 3-amino-N-[(3R)-6-fluoro-7-{9- 484 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, ++++ +++ oxa-3,7- J = 8.4 Hz, 1H), 7.58 (br s, 1H), 7.32 (d, diazabicyclo[3.3.1]nonan-3-yl}- J = 8.4 Hz, 1H), 7.23 (br s, 2H), 6.96 (d, 3,4-dihydro-2H-1-benzopyran-3- J = 12.8 Hz, 1H), 6.43 (d, J = 7.6 Hz, yl]-6-methylthieno[2,3- 1H), 4.30-4.22 (m, 1H), 4.19-4.11 (m, b]pyridine-2-carboxamide 1H), 3.85-3.82 (m, 1H), 3.66-3.64 (m, 2H), 3.40-3.37 (m, 2H), 3.17-3.09 (m, 4H), 2.98-2.89 (m, 4H), 2.58 (s, 3H). 107 7-amino-N-[(3R)-7-{3,8- 487 (DMSO-d6 300 MHz) δ (ppm): 8.67 (s, ++++ ++++ diazabicyclo[3.2.1]octan-3-yl}- 1H), 7.90 (d, J = 6.9 Hz, 1H), 7.00 (br s, 5,8-difluoro-3,4-dihydro-2H-1- 2H), 6.37-6.31 (m, 1H), 4.40-4.24 (m, benzopyran-3-yl]-3- 2H), 4.00-3.94 (m, 1H), 3.40-3.33 (m, methylthieno[2,3-b]pyrazine-6- 2H), 3.08-3.05 (m, 2H), 2.99-2.91 (m, carboxamide 1H), 2.84-2,73 (m, 3H), 2.65 (s, 3H), 1.80-1.73 (m, 2H), 1.66-1.65 (m, 2H). 108 6-amino-N-[(3R)-7-{3,8- 492 (DMSO-d6 300 MHz) δ (ppm): 7.52 (d, ++++ +++ diazabicyclo[3.2.1]octan-3-yl}- J = 7.2 Hz, 1H), 7.15 (br s, 2H), 6.15 (d, 5,6-difluoro-3,4-dihydro-2H-1- J = 5.4 Hz, 1H), 4.27-4.24 (m, 1H), 4.15- benzopyran-3-yl]-2- 4.12 (m, 1H), 3.87-3.81 (m, 1H), 3.39- methylthieno[2,3-d][1,3]thiazole- 3.33(m, 2H), 3.08-3.05 (m, 1H), 2.94- 5-carboxamide 2.87 (m, 1H), 2.79-2.72 (m, 6H), 1.79- 1.65 (m, 4H). 109 3-amino-N-[(2S)-7-cyano-6-{9- 489 (DMSO-d6, 400 MHz) δ (ppm): 8.30 (d, ++++ ++ oxa-3,7- J = 8.4 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), diazabicyclo[3.3.1]nonan-3-yl}- 7.53 (s, 1H), 7.31 (d, J = 8.0 Hz) 7.17 (br 1,2,3,4-tetrahydronaphthalen-2- s, 2H), 6.96 (s, 1H), 4.19-4.09 (m, 1H), yl]-6-methylthieno[2,3- 3.70-3.65 (m, 2H), 3.51-3.48 (m, 2H), b]pyridine-2-carboxamide 3.29-3.19 (m, 2H), 3.18-2.65 (m, 9H), 2.58 (s, 3H), 1.99-1.90 (m, 1H), 1.89- 1.70 (m, 1H). 110 3-amino-N-[(3R)-7-[(1S,4S)-2,5- 472 (DMSO-d6 400 MHz) δ (ppm): 8.33 (d, ++++ +++ diazabicyclo[2.2.1]heptan-2-yl]- J = 8.4 Hz, 1H), 7.64 (d, J = 7.2 Hz, 1H), 5,8-difluoro-3,4-dihydro-2H-1- 7.31 (d, J = 8.4 Hz, 1H), 7.24(br s, 2H), benzopyran-3-yl]-6- 6.21-6.15 (m, 1H), 4.26-4.23 (m, 3H), methylthieno[2,3-b]pyridine-2- 3.95-3.88 (m, 1H), 3.61-3.54(m, 2H), carboxamide 3.01-2.72 (m, 5H), 2.58 (s, 3H), 1.73 (d, J = 9.6 Hz, 1H), 1.60 (d, J = 9.3 Hz, 1H). 111 3-amino-N-[(3R)-7-[(1R,4R)-2,5- 472 (DMSO-d6, 400 MHz) δ (ppm): 8.34 (d, ++++ +++ diazabicyclo[2.2.1]heptan-2-yl]- J = 8.4 Hz, 1H), 7.64 (br s, 1H), 7.32 (d, 5,8-difluoro-3,4-dihydro-2H-1- J = 8.0 Hz, 1H), 7.24 (br s, 2H), 6.20- benzopyran-3-yl]-6- 6.15 (m, 1H), 4.31-4.23 (m, 3H), 3.92- methylthieno[2,3-b]pyridine-2- 3.87 (m, 1H), 3.59-3.57 (m, 1H), 3.57- carboxamide 3.53 (m, 1H), 3.00-2.97 (m, 1H), 2.91- 2.77 (m, 4H), 2.58-2.55 (s, 3H), 1.76- 1.72 (m, 1H), 1.62-1.55 (m, 1H). 112 3-amino-N-[(3R)-7-[(1S,4S)-2,5- 472 (DMSO-d6, 400 MHz) δ (ppm): 8.34 (d, ++++ ++ diazabicyclo[2.2.1]heptan-2-yl]- J = 8.4 Hz, 1H), 7.61 (d, J = 7.2 Hz, 1H), 5,6-difluoro-3,4-dihydro-2H-1- 7.31 (d, J = 8.0 Hz, 1H), 7.24 (br s, 2H), benzopyran-3-yl]-6- 6.13 (d, J = 6.4 Hz, 1H), 4.49 (s, 1H), methylthieno[2,3-b]pyridine-2- 4.28-4.15 (m, 3H), 3.89-3.84 (m, 1H), carboxamide 3.67-3.65 (m, 2H), 3.23-3.14 (m, 1H), 2.99-2.74 (m, 2H), 2.58 (s, 3H), 2.14 (d, J = 10.8 Hz, 1H), 1.92 (d, J = 10.0 Hz, 1H). 113 3-amino-N-[(3R)-7-{9 9-difluoro- 501 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, ++++ ++ 3,7-diazabicyclo[3.3.1]nonan-3- J = 8.4 Hz, 1H), 7.58 (d, J = 7.2 Hz, 1H), yl}-2H b,3H,4H-pyrano[2,3- 7.38-7.31(m, 2H), 7.23 (br s, 2H), 6.44 b]pyridin-3-yl]-6- (d, J = 8.4 Hz, 1H), 4.29-4.23 (m, 4H), methylthieno[2,3-b]pyridine-2- 4.02-3.98 (m, 1H), 3.19-3.14 (m, 4H), carboxamide 2.98-2.85 (m, 4H), 2.59 (s, 3H), 2.16- 2.14 (m, 2H), 1.85 (br s, 1H). 114 3-amino-N-[(3R)-7-{9,9-difluoro- 501 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, ++++ 3,7-diazabicyclo[3.3.1]nonan-3- J = 8.4 Hz, 1H), 7.88 (s, 1H), 7.60 (br s, yl}-2H,3H,4H-pyrano[3,2- 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.24 (br s, c]pyridin-3-yl]-6- 2H), 6.22 (s, 1H), 4.31-4.21(m, 4H), methylthieno[2,3-b]pyridine-2- 3.94-3.89 (m, 1H), 3.19-3.13 (m, 4H), carboxamide 2.97-2.80 (m, 4H), 2.58 (s, 3H), 2.14- 2.10 (m, 2H). 115 3-amino-N-[(3R)-7-[(3S,4S)-3- 468 (DMSO-d6 400 MHz) δ (ppm): 8.33 (d, ++++ ++ amino-4-ethoxypyrrolidin-1-yl]- J = 8.4 Hz, 1H), 7.50 (br s, 1H), 7.32 (d, 3,4-dihydro-2H-1-benzopyran-3- J = 8.0 Hz, 1H), 7.21 (br s, 2H), 6.87 (d yl]-6-methylthieno[2,3- J = 8.4 Hz, 1H), 6.10 (d, J = 8.4 Hz, 1H), b]pyridine-2-carboxamide 5.90 (s, 1H), 4.33-4.31 (m, 1H), 4.15- 4.12 (m, 1H), 3.80-3.77 (m, 1H), 3.76- 3.74 (m, 1H), 3.54-3.45 (m, 3H), 3.38- 3.3.37 (m, 2H), 3.30 (s, 3H), 3.13-3.11 (m, 1H), 3.09-3.06 (m, 1H), 2.88-2.81 (m, 2H), 2.58 (s, 3H), 1.81 (br s, 2H), 1.12 (d, J = 8.4 Hz, 3H). 116 3-amino-N-[(2S)-6-[(3S,4S)-3- 452 (DMSO-d6 400 MHz) δ (ppm): 8.30 (d, +++ ++ amino-4-methoxypyrrolidin-1- J = 8.4 Hz, 1H), 7.53 (br s, 1H), 7.30 (d, yl}-1,2,3,4- J = 8.0 Hz, 1H), 7.15 (br s, 2H), 6.86 (d tetrahydronaphthalen-2-yl]-6- J = 8.4 Hz, 1H), 6.32-6.29 (m, 1H), 6.22 methylthieno[2,3-b]pyridine-2- (d, J = 2.0 Hz, 1H), 4.14-4.08 (m, 1H), carboxamide 3.64-3.62 (m, 1H), 3.52-3.48 (m, 1H), 3.43-3.34 (m, 2 H), 3.30 (s, 3H), 3.13- 3.10 (m, 1H), 2.91-2.71(m, 5H), 2.58 (s 3H), 1.98-1.95 (m, 1H), 1.77-1.72 (m, 1H). 117 7-amino-N-[(3R)-7-[(3S,4S)-3- 455 (DMSO-d6, 300 MHz) δ (ppm): 8.66 (s, ++++ ++ amino-4-methoxypyrrolidin-1- 1H), 7.75 (br s, 1H), 6.97 (br s, 2H), yl]-3,4-dihydro-2H-1- 6.88 (d, J = 8.4 Hz, 1H), 6.13-6.09 (m, benzopyran-3-yl]-3- 1H), 5.92 (d, J = 2.1 Hz, 1H), 4.32-4.25 methylthieno[2,3-b]pyrazine-6- (m, 1H), 4.19-4.13 (m, 1H), 3.84-3.81 carboxamide (m, 1H), 3.64-3.62 (m, 1H), 3.49-3.37 (m, 3H), 3.30 (s, 3H), 3.14-3.10 (m, 1H), 2.91-2.84 (m, 3H), 2.66 (s, 3H), 1.72 (br s, 1H). 118 6-amino-N-[(3R)-7-[(3S,4S)-3- 460 (DMSO-d6, 400 MHz) δ (ppm): 7.40 (br +++ ++ amino-4-methoxypyrrolidin-1- s, 1H), 7.13 (s, 2H), 6.87-6.85 (m, 1H), yl]-3,4-dihydro-2H-1- 6.10-6.08 (m, 1H), 5.90 (s, 1H), 4.25- benzopyran-3-yl]-2- 4.22 (m, 1H), 4.12-4.10 (m 1H), 3.77- methylthieno[2,3-d][1,3]thiazole- 3.73 (m, 1H), 3.63-3.61(m, 1H), 3.49- 5-carboxamide 3.40 (m, 3H), 3.29 (s, 3H), 3.11-3.09 (m, 1H), 2.89-2.87 (m, 1H), 2.80-2.78 (m, 5H), 1.77 (br s, 2H). 119 3-amino-N-[(3R)-7-[(3S,4S)-3- 468 (DMSO-d6 300 MHz) δ (ppm): 8.33 (d, +++ ++ amino-4-methoxypiperidin-1-yl}- J = 8.4 Hz, 1H), 7.53 (d, J = 7.5 Hz, 1H), 3,4-dihydro-2H-1-benzopyran-3- 7.32 (d, J = 8.4 Hz, 1H), 7.22 ( br s, 2H), yl]-6-methylthieno[2,3- 6.93 (d, J = 8.4 Hz, 1H), 6.54-6.50 (m, b]pyridine-2-carboxamide 1H), 6.33 (d, J = 2.1 Hz, 1H), 4.32-4.28 (m, 1H), 4.18-4.15 (m, 1H), 3.86-3.79 (m, 1H), 3.70-3.55 (m, 2H), 3.38 (s, 3H), 3.23-3.21 (m, 1H), 3.02-2.98 (m, 1H), 2.88-2.75 (m, 4H), 2.59 (s, 3H), 2.12- 2.08 (m, 1H), 2.08-2.02 (m 1H), 1.42- 1.32 (m, 1H). 120 3-amino-N-[(3R)-7-[(3R,4R)-3- 468 (DMSO-d6 400 MHz) δ (ppm): 8.33 (d, ++++ ++ amino-4-methoxypiperidin-1-yl]- J = 8.0 Hz, 1H), 7.53 (d, J = 7.2 Hz, 1H), 3,4-dihydro-2H-1-benzopyran-3- 7.32 (d, J = 8.4 Hz, 1H), 7.21 (br s, 2H), yl]-6-methylthieno[2,3- 6.91 (d, J = 8.4 Hz, 1H), 6.51-6.48 (m, b]pyridine-2-carboxamide 1H), 6.31 (d, J = 2.4 Hz, 1H), 4.28-4.26 (m, 1H), 4.16-4.13 (m, 1H), 3.82-3.77 (m, 1H), 3.55-3.51 (m, 2H), 3.35 (s, 3H), 2.95-2.83 (m, 3H), 2.72-2.65 (m, 2H), 2.58 (s, 3H), 2.50-2.41 (m, 1H), 2.08- 2.02 (m, 1H), 1.75-1.55 (br s, 2H), 1.33- 1.30 (m, 1H). 121 3-amino-N-[(3R)-7-[(3S,4R)-3- 454 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, ++++ ++ amino-4-methoxypyrrolidin-1- J = 8.0 Hz, 1H), 7.51 (br s, 1H), 7.32 (d, yl]-3,4-dihydro-2H-1- J = 8.0 Hz, 1H), 7.22 (br s, 2H), 6.87 (d, benzopyran-3-yl]-6- J = 8.8 Hz, 1H), 6.12-6.07 (m, 1H), 5.89 methylthieno[2,3-b]pyridine-2- (s, 1H), 4.30-4.23 (m, 1H), 4.15-4.12 (m, carboxamide 1H), 3.81-3.73 (m, 2H), 3.49-3.48 (m, 1H), 3.30-3.28 (m, 6H), 2.85-2.81 (m, 3H), 2.59 (s, 3H), 1.26 (br s, 2H). 122 3-amino-N-[(3R)-7-[(3R,4S)-3- 454 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, ++++ ++ amino-4-methoxypyrrolidin-1- J = 8.0 Hz, 1H), 7.50 (br s, 1H), 7.32 (d, yl]-3,4-dihydro-2H-1- J = 8.4 Hz, 1H), 7.22 (s, 2H), 6.87 (d, J = benzopyran-3-yl]-6- 8.4 Hz, 1H), 6.09-6.07 (m, 1H), 5.89 methylthieno[2,3-b]pyridine-2- (s, 1H), 4.29-4.28 (m, 1H), 4.15-4.13 (m, carboxamide 1H), 3.81-3.74 (m, 2H), 3.51-3.48 (m, 1H), 3.30-3.27 (m, 6H), 2.85-2.81 (m, 3H), 2.59 (s, 3H), 1.24 (br s, 2H). 123 3-amino-6-methyl-N-[(3R)-7- 409 (DMSO-d6 400 MHz) δ (ppm): 8.34 (d, ++++ ++ [(1s,3S)-3-aminocyclobutyl]-3,4- J = 8.4 Hz, 1H), 7.58 (d, J = 7.2 Hz, 1H), dihydro-2H-1-benzopyran-3- 7.32 (d, J = 8.4 Hz, 1H), 7.28-7.20 (m, yl]thieno[2,3-b]pyridine-2- 2H), 7.03 (d, J = 8.0 Hz, 1H), 6.79 (d, J = carboxamide 8.4 Hz, 1H), 6.67-6.65 (m, 1H), 4.33- 4.25 (m, 1H), 4.20-4.17 (d, J = 10.4 Hz, 1H), 3.86-3.81 (m, 1H), 3.55-3.52 (m, 1H), 3.49-3.44 (m, 1H), 2.98-2.89(m, 2H), 2.58-2.53 (s, 3H), 2.30-2.20 (m, 2H), 2.18-2.07 (m, 2H). 124 3-amino-6-methyl-N-[(3R)-7- 409 (DMSO-d6, 400 MHz) δ (ppm): 8.31 (d, ++++ ++ [(1r,3r)-3-aminocyclobutyl]-3,4- J = 8.4 Hz, 1H), 7.32 (d, J = 8 Hz, 1H), dihydro-2H-1-benzopyran-3- 7.02 (d, J = 7.6 Hz, 1H), 6.79-6.76 (m, yl]thieno[2,3-b]pyridine-2- 1H), 6.69-6.68 (s, 1H), 4.33-4.25 (m carboxamide 1H), 4.18-4.16 (d, J = 10 Hz, 1H), 3.86- 3.81 (m, 1H), 3.29-3.21 (m, 1H), 2.95- 2.88(m, 3H), 2.57-2.55 (s, 3H), 2.54- 2.52 (m, 2H), 1.78-1.76 (m, 2H). 125 3-amino-6-methyl-N-[(3R)-7-{3- 465 (DMSO-d6 400 MHz) δ (ppm): 8.33 (d, ++++ +++ oxa-9-azabicyclo[3.3.1]nonan-7- J = 8.4 Hz, 1H), 7.58 (d, J = 7.6 H, 1H), yl}-3,4-dihydro-2H-1- 7.32 (d, J = 8.0 Hz, 1H), 7.24 (br s, 2H), benzopyran-3-yl]thieno[2,3- 7.02 (d, J = 8.0 Hz, 1H), 6.78 (d, J = 8.0 b]pyridine-2-carboxamide Hz, 1H), 6.68 (s, 1H), 4.33-4.17(m, 2H), 3.86-3.75 (m, 6H), 2.99-2.83 (m, 4H), 2.59 (s, 3H), 2.43 (br s, 1H), 1.87- 1.81(m, 4H). 126 3-amino-N-[(3R)-6-cyano-7- 493 (DMSO-d6, 400 MHz) δ (ppm): 8.32 (d, ++++ ++++ {3,8-diazabicyclo[3.2.1]octan-3- J = 8.0 Hz, 1H), 7.70 (d, J = 6.4 Hz, 1H), yl}-5-fluoro-3,4-dihydro-2H-1- 7.31 (d, J = 8.4 Hz, 1H), 7.24 (br s, 2H), benzopyran-3-yl]-6- 6.29 (s, 1H), 4.30-4.25 (m, 2H), 4.06- methylthieno[2,3-b]pyridine-2- 4.01 (m, 1H), 3.48 (s, 2H), 3.33-3.28 (s, 3H), carboxamide 2H), 2.96-2.67 (m, 4H), 2.58 (s, 3H), 1.88-1.87 (m, 2H), 1.67-1.65 (m, 2H). 127 3-amino-N-[(3R)-6-cyano-5- 509 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, ++++ +++ fluoro-7-{9-oxa-3,7- J = 8.4 Hz, 1H), 7.66 (d, J = 6.8 Hz, 1H), diazabicyclo[3.3.1]nonan-3-yl}- 7.31 (d, J = 8.4 Hz, 1H), 7.28 (br s, 2H), 3,4-dihydro-2H-1-benzopyran-3- 6.43 (s, 1H), 4.34-4.28 (m, 2H), 4.10- yl]-6-methylthieno[2,3- 4.05 (m, 1H), 3.71 (s, 2H), 3.57-3.51 (m, b]pyridine-2-carboxamide 2H), 3.29-3.26 (m, 2H), 3.16-3.12 (m, 2H), 3.04-2.94(m, 3H), 2.86-2.82 (m, 1H), 2.58 (s, 3H). 128 3-amino-N-[(3R)-7-[(3S,4S)-4- 468 (DMSO-d6 400 MHz) δ (ppm): 8.32 (d, ++++ ++ amino-3-methoxypiperidin-1-yl]- J = 8.0 Hz, 1H), 7.53 (d, J = 7.2 Hz, 1H), 3,4-dihydro-2H-1-benzopyran-3- 7.31 (d, J = 8.4 Hz, 1H), 7.22 (s, 2H), yl]-6-methylthieno[2,3- 6.92 (d, J = 8.8 Hz, 1H), 6.55-6.53 (m b]pyridine-2-carboxamide 1H), 6.35 (d, J = 2.0 Hz, 1H), 4.28 (br s, 1H), 4.17-4.13 (m, 1H), 3.86-3.77 (m, 2H), 3.53-3.50 (m, 1H), 3.39 (s, 3H), 2.89-2.83 (m, 3H), 2.67-2.55 (m, 6H), 2.38-2.35 (m, 1H), 1.88-1.70 (m, 2H), 1.38-1.29 (m, 1H). 129 3-amino-N-[(3R)-7-[(3R,4R)-4- 468 (DMSO-d6, 400 MHz) δ (ppm): 8.32 (d, ++++ ++ amino-3-methoxypiperidin-1-yl]- J = 8.0 Hz, 1H), 7.53 (br s, 1H), 7.31 (d, 3,4-dihydro-2H-1-benzopyran-3- J = 8.4 Hz, 1H), 7.22 (br s, 2H), 6.91 (d, yl]-6-methylthieno[2,3- J = 8.4 Hz, 1H), 6.55-6.53 (m, 1H), 6.35 b]pyridine-2-carboxamide (d, J = 2.4 Hz, 1H), 4.30-4.26 (m, 1H), 4.17-4.13 (m, 1H), 3.85-3.77 (m, 2H), 3.54-3.51 (m, 1H), 3.39 (s, 3H), 2.90- 2.84 (m, 3H), 2.66-2.53 (m, 6H), 2.37- 2.32 (m, 1H), 1.79-1.68 (m, 2H), 1.36- 1.32 (m, 1H). 130 7-amino-N-[(2S)-6-[(3S,4S)-3- 453 (DMSO-d6, 400 MHz) δ (ppm): 8.65 (s, +++ ++ amino-4-methoxypyrrolidin-1- 1H), 7.79 (d, J = 8.0 Hz, 1H), 6.91(br s, yl]-1,2,3,4- 2H), 6.87 (d, J = 8.4 Hz, 1H), 6.32 (dd, J = tetrahydronaphthalen-2-yl]-3- 8.0, 2.0 Hz, 1H), 6.24 (s, 1H), 4.16- methylthieno[2,3-b]pyrazine-6- 4.11 (m, 1H), 3.65-3.63 (m, 1H), 3.53- carboxamide 3.49 (m, 1H), 3.42-3.35 (m, 2H), 3.32 (s, 3H), 3.14-3.11 (m, 1H), 2.92-2.79 (m, 5H), 2.65 (s, 3H), 2.10-1.90 (m, 3H), 1.79-1.73 (m, 1H). 131 N-[(2S)-6-[(3S,4S)-3-amino-4- 435 (DMSO-d6, 400 MHz) δ (ppm): 8.87 (d, + + methoxypyrrolidin-1-yl]-1,2,3,4- J = 8.4 Hz, 1H), 8.45 (s, 1H), 8.09 (d, J = tetrahydronaphthalen-2-yl]-7- 3.2 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), ethyl-7H-pyrrolo[2,3- 6.75 (d, J = 3.6 Hz, 1H), 6.37-6.29 (m, c]pyridazine-3-carboxamide 1H), 6.29 (s, 1H), 4.52 (dd, J = 14.4, 7.2 Hz, 2H), 4.33-4.27 (m, 1H), 3.64-3.63 (m, 1H), 3.54-3.50 (m, 1H), 3.37-3.33 (m, 2H), 3.31 (s, 3H), 3.15-3.13 (m, 1H), 2.95-2.79 (m, 5H), 2.01-1.86 (m, 2H), 1.48 (t, J = 7.2 Hz, 3H). 132 N-[(2S)-6-[(3S,4S)-3-amino-4- 434 (DMSO-d6 400 MHz) δ (ppm): 8.77 (s, ++ + methoxypyrrolidin-1-yl]-1,2,3,4- 1H), 8.47 (s, 1H), 8.41 (d, J = 7.6 Hz, tetrahydronaphthalen-2-yl]-1- 1H), 7.68 (d, J = 3.6 Hz, 1H), 6.89 (d, J = ethyl-1H-pyrrolo[2,3-b]pyridine- 8.4 Hz, 1H), 6.59 (d, J = 3.6 Hz, 1H), 5-carboxamide 6.34-6.32 (m, 1H), 6.24 (s, 1H), 4.33 (dd, J = 14.4, 7.2 Hz, 2H), 4.16-4.12 (m, 1H), 3.65-3.64 (m, 1H), 3.53-3.43 (m 1H), 3.43-3.35 (m, 2H), 3.31 (s, 3H), 3.15-3.12 (m, 1H), 2.95-2.90 (m, 2H), 2.90-2.81 (m, 2H), 2.2.78-2.71 (m, 1H), 2.10-2.01 (m, 1H), 1.92 (br s, 2H), 1.83- 1.67 (m, 1H), 1.40 (t, J = 7.2 Hz, 3H). 133 6-amino-N-[(2S)-6-[(3S,4S)-3- 458 (DMSO-d6 400 MHz) δ (ppm): 7.43 (d, +++ + amino-4-methoxypyrrolidin-1- J = 7.6 Hz, 1H), 7.07(br s, 2H), 6.86 (d yl]-1,2,3,4- J = 8.0 Hz, 1H), 6.31 (dd, J = 8.4, 2.4 tetrahydronaphthalen-2-yl]-2- Hz, 1H), 6.22 (s, 1H), 4.12-4.04 (m, 1H), methylthieno[2,3-d][1,3]thiazole- 3.64-3.62 (m, 1H), 3.53-3.50 (m, 1H), 5-carboxamide 3.48-3.32 (m, 2H), 3.30 (s, 3H), 3.14- 3.11 (m, 1H), 2.92-2.89 (m, 1H), 2.84- 2.78 (m, 6H), 2.72-2.68 (m, 1H), 1.96- 1.94 (m, 1H), 1.85-1.65 (m, 3H). 134 3-amino-N-[(2S)-6-[(3S,4S)-3- 468 (DMSO-d6 400 MHz) δ (ppm): 8.30 (d, ++ + amino-4-methoxypyrrolidin-1- J = 7.2 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), yl]-1,2,3,4- 7.13 (br s, 2H), 6.87 (dd, J = 8.4, 2.0 Hz, tetrahydronaphthalen-2-yl]-6- 2H), 6.32 (dd, J = 8.0, 2.0 Hz, 1H), 6.22 methoxythieno[2,3-b]pyridine-2- (s, 1H), 4.14-4.06 (m, 1H), 3.94 (s, 3H), carboxamide 3.65-3.63 (m, 1H), 3.52-3.47 (m, 1H), 3.42-3.35 (m, 2H), 3.30 (s, 3H), 3.14- 3.12 (m, 1H), 2.93-2.69 (m, 5H), 2.01- 1.91 (m, 1H), 1.85-1.69 (m, 3H). 135 3-amino-N-[(2S)-6-[(3S,4S)-3- 486 (DMSO-d6, 400 MHz) δ (ppm): 8.32 (d, ++ + amino-4-methoxypyrrolidin-1- J = 10.8 Hz, 1H), 7.49 (d, J = 7.6 Hz, yl]-1,2,3,4- 1H), 7.08 (br s, 2H), 6.87 (d, J = 8.4 tetrahydronaphthalen-2-yl]-5- Hz, 1H), 6.31 (dd, J = 8.0, 2.0 Hz, 1H), fluoro-6-methoxythieno[2,3- 6.23 (s, 1H), 4.09-4.03 (m, 4H), 3.65- b]pyridine-2-carboxamide 3.63 (m, 1H), 3.53-3.52 (m, 1H), 3.48- 3.42 (m, 2H), 3.41 (s, 3H), 3.14-3.11 (m, 1H), 2.92-2.71 (m, 5H), 2.01-1.95 (m, 1H), 1.85-1.68 (m, 3H). 136 3-amino-N-[(2S)-6-[(3S,4S)-3- 470 (DMSO-d6, 400 MHz) δ (ppm): 8.31 (d, + + amino-4-methoxypyrrolidin-1- J = 8.4 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), yl]-8-fluoro-1,2,3,4- 7.31 (d, J = 8.0 Hz, 1H), 7.17 (br s, 2H), tetrahydronaphthalen-2-yl]-6- 6.14 (d, J = 12.4 Hz, 1H), 6.09 (s, 1H), methylthieno[2,3-b]pyridine-2- 4.14-4.08 (m, 1H), 3.63-3.61 (m, 1H), carboxamide 3.54-3.41 (m, 3H), 3.37 (s, 3H), 3.17- 3.12 (m, 1H), 3.95-3.79 (m, 4H), 2.59- 2.52 (m, 4H), 2.00-1.95 (m, 1H), 1.81- 1.69 (m, 3H). 137 3-amino-N-[(2R)-6-[(3S,4S)-3- 470 (DMSO-d6, 400 MHz) δ (ppm): 8.31 (d, +++ + amino-4-methoxypyrrolidin-1- J = 8.4 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), yl]-8-fluoro-1,2,3,4- 7.31 (d, J = 8.4 Hz, 1H), 7.17 (br s, 2H), tetrahydronaphthalen-2-yl]-6- 6.14 (d, J = 12.8 Hz, 1H), 6.09 (s, 1H), methylthieno[2,3-b]pyridine-2- 4.14-4.08 (m, 1H), 3.63-3.61 (m, 1H), carboxamide 3.54-3.41 (m, 3H), 3.37 (s, 3H), 3.17- 3.12 (m, 1H), 3.95-3.79 (m, 4H), 2.59 (s, 3H), 2.57-2.51 (m, 1H), 1.97-1.94 (m, 1H), 1.81-1.69 (m, 3H). 138 N-[(2S)-6-[(3S,4S)-3-amino-4- 453 (DMSO-d6 400 MHz) δ (ppm): 8.98 (d, + + methoxypyrrolidin-1-yl]-8-fluoro- J = 8.4 Hz, 1H), 8.46 (s, 1H), 8.10 (d, J = 1,2,3,4-tetrahydronaphthalen-2- 3.2 Hz, 1H), 6.75 (d, J = 3.6 Hz, 1H), yl]-7-ethyl-7H-pyrrolo[2,3- 6.16 (d, J = 12.4 Hz, 1H), 6.12 (s, 1H), c]pyridazine-3-carboxamide 4.53 (dd, J = 14.4, 7.2 Hz, 2H), 4.33- 4.25 (m, 1H), 3.65-3.63 (m, 1H), 3.55- 3.45 (m, 1H), 3.42-3.40 (m, 1H), 3.35- 3.32 (m, 1H), 3.30 (s, 3H), 3.17-3.14 (m, 1H), 2.98-2.80 (m, 4H), 2.70-2.61 (m, 1H),2.13-1.85 (m, 2H), 1.72 (br s, 2H), 1.49 (t, J = 7.2 Hz, 3H). 139 N-[(2R)-6-[(3S,4S)-3-amino-4- 453 (DMSO-d6, 400 MHz) δ (ppm): 8.98 (d, + + methoxypyrrolidin-1-yl]-8-fluoro- J = 8.4 Hz, 1H), 8.46 (s, 1H), 8.10 (d, J = 1,2,3,4-tetrahydronaphthalen-2- 3.6 Hz, 1H), 6.75 (d, J = 3.2 Hz, 1H), yl]-7-ethyl-7H-pyrrolo[2,3- 6.16 (d, J = 12.4 Hz, 1H), 6.12 (s, 1H), c]pyridazine-3-carboxamide 4.53 (dd, J = 14.4, 7.2 Hz, 2H), 4.33- 4.25 (m, 1H), 3.65-3.63 (m, 1H), 3.55- 3.45 (m, 1H), 3.42-3.40 (m, 1H), 3.35- 3.32 (m, 1H), 3.30 (s, 3H), 3.16-3.14 (m, 1H), 2.98-2.80 (m, 4H), 2.70-2.61 (m, 1H),2.13-1.85 (m, 2H), 1.71 (br s, 2H), 1.49 (t, J = 7.2 Hz, 3H). 140 3-amino-N-[(3R)-7-[(3S,4S)-3- 480 (DMSO-d6, 400 MHz) δ (ppm): 8.32 (d, ++++ ++ amino-4-cyclopropoxypyrrolidin- J = 8.0 Hz, 1H), 7.49 (br s, 1H), 7.32 (d, 1-yl]-3,4-dihydro-2H-1- J = 8.4 Hz, 1H), 7.21 (br s, 2H), 6.87 (d benzopyran-3-yl]-6- J = 8.4 Hz, 1H), 6.10 (d, J = 8.8 Hz, 1H), methylthieno[2,3-b]pyridine-2- 5.91 (s, 1H), 4.30-4.26 (m, 1H), 4.16- carboxamide 4.12 (m, 1H), 3.84-3.76 (m, 2H), 3.54- 3.50 (m, 1H), 3.45-3.37 (m, 3H), 3.15- 3.13 (m, 1H), 2.89-2.82 (m, 3H), 2.59 (s, 3H), 1.80 (br s, 2H), 0.52-0.47 (m, 4H). 141 3-amino-N-[(3R)-7-[(3S,4S)-3- 494 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, ++++ +++ amino-4-cyclobutoxypyrrolidin- J = 8.4 Hz, 1H), 7.48 (d, J = 7.2 Hz, 1H), 1-yl]-3,4-dihydro-2H-1- 7.32 (d, J = 8.4 Hz, 1H), 7.21 (br s, 2H), benzopyran-3-yl]-6- 6.87 (d, J = 8.0 Hz, 1H), 6.09 (d, J = 8.0 methylthieno[2,3-b]pyridine-2- Hz, 1H), 5.90 (s, 1H), 4.28 (br s, 1H), carboxamide 4.15-4.13 (m, 1H), 4.07-4.03 (m, 1H), 3.81-3.76 (m, 1H), 3.69 (s, 1H), 3.49- 3.46 (m, 1H), 3.37-3.35 (m, 2H), 3.04 (d, J = 8.0 Hz,, 1H), 2.89-2.82 (m, 3H), 2.59 (s, 3H), 2.18-2.08(m, 2H), 1.87-1.40 (m, 6H). 142 3-amino-N-[(6S)-2-[(3S,4S)-3- 467 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, ++ + amino-4-ethoxypyrrolidin-1-yl]- J = 10.4 Hz, 1H), 7.56 (br s, 1H), 7.31 5,6,7,8-tetrahydroquinolin-6-yl]- (d, J = 8.4 Hz, 1H), 7.20-7.16 (m, 3H), 6-methylthieno[2,3-b]pyridine-2- 6.22 (d, J = 8.8 Hz, 1H), 4.13-4.10 (m, carboxamide 1H), 3.72-3.70 (m, 1H), 3.64-3.61 (m, 1H), 3.52-3.40 (m, 4H), 3.32-3.29 (m, 1H), 3.12-3.10 (m, 1H), 2.81-2.68 (m, 4H), 2.59 (s, 3H), 2.05-1.97 (m, 1H), 1.87-1.67 (m, 3H), 1.12 (t, J = 8.0 Hz, 3H). 143 3-amino-N-[(2S)-6-[(3S,4R)-3- 452 (DMSO-d6 400 MHz) δ (ppm): 8.30 (d, ++++ ++ amino-4-methoxypyrrolidin-1- J = 8.0 Hz, 1H), 7.52 (d, J = 9.2 Hz, 1H), yl]-1,2,3,4- 7.31 (d, J = 8.0 Hz, 1H), 7.15 (br s, 2H), tetrahydronaphthalen-2-yl]-6- 6.86 (d, J = 8.0 Hz, 1H), 6.30-6.28 (m, methylthieno[2,3-b]pyridine-2- 1H), 6.21 (s, 1H), 4.12-4.09 (m, 1H), carboxamide 3.75-3.70 (m, 1H), 3.52-3.50 (m, 1H), 3.35 3.25 (m, 6H), 2.86-2.68 (m, 5H), 2.59 (s, 3H), 1.98-1.95 (m, 1H), 1.77- 1.71 (m, 1H), 1.57 (br s, 2H). 144 3-amino-N-[(2S)-6-[(3S,4R)-3- 452 (DMSO-d6 400 MHz) δ (ppm): 8.30 (d, +++ ++ amino-4-methoxypyrrolidin-1- J = 8.0 Hz, 1H), 7.52 (d, J = 9.2 Hz, 1H), yl]-1,2,3,4- 7.31 (d, J = 8.0 Hz, 1H), 7.15 (br s, 2H), tetrahydronaphthalen-2-yl]-6- 6.86 (d, J = 8.0 Hz, 1H), 6.30-6.28 (m, methylthieno[2,3-b]pyridine-2- 1H), 6.21 (s, 1H), 4.12-4.09 (m, 1H), carboxamide 3.75-3.70 (m, 1H), 3.52-3.50 (m, 1H), 3.35 3.25 (m, 6H), 2.86-2.68 (m, 5H), 2.59 (s, 3H), 1.98-1.95 (m, 1H), 1.77- 1.57 (m, 3H). 145 3-amino-N-[(3R)-7-[(3S,4R)-3- 472 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, ++++ ++ amino-4-methoxypyrrolidin-1- J = 8.4 Hz, 1H), 7.55 (br s, 1H), 7.32 (d, yl]-5-fluoro-3,4-dihydro-2H-1- J = 8.4 Hz, 1H), 7.23 (br s, 2H), 5.94 (d, benzopyran-3-yl]-6- J = 14.0 Hz, 1H), 5.77 (s, 1H), 4.28-4.24 methylthieno[2,3-b]pyridine-2- (m, 1H), 4.18-4.16 (m, 1H), 3.86-3.81 carboxamide (m, 1H), 3.74-3.73 (m, 1H), 3.50-3.47 (m, 1H), 3.33(s, 3H), 3.28-3.22 (m, 3H), 2.87-2.83(m, 2H), 2.75-2.71 (m, 1H), 2.59 (s, 3H), 1.66 (br s, 2H). 146 3-amino-N-[(3R)-7-1(3R,4S)-3- 472 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, ++++ ++ amino-4-methoxypyrrolidin-1- J = 8.4 Hz, 1H), 7.55 (br s, 1H), 7.32 (d, yl]-5-fluoro-3,4-dihydro-2H-1- J = 8.4 Hz, 1H), 7.22 (br s, 2H), 5.94 (d benzopyran-3-yl]-6- J = 12.4 Hz, 1H), 5.77 (s, 1H), 4.29-4.26 methylthieno[2,3-b]pyridine-2- (m, 1H), 4.17-4.15 (m, 1H), 3.86-3.81 carboxamide (m, 1H), 3.74-3.73 (m, 1H), 3.49-3.46 (m, 1H), 3.34-3.22(m, 6H), 2.87-2.83 (m, 2H), 2.75-2.71 (m, 1H), 2.59 (s, 3H), 1.66 (br s, 2H). 147 7-amino-N-[(3R)-7-[(3R,4R)-3- 455 (DMSO-d6, 400 MHz) δ (ppm): 8.65 (s, +++ ++ amino-4-methoxypyrrolidin-1- 1H), 77.3 (d, J = 7.6 Hz, 1H), 6.96 (br s, yl]-3,4-dihydro-2H-1- 2H), 6.87 (d, J = 8.0 Hz, 1H), 6.08 (d, J = benzopyran-3-yl]-3- 8.0 Hz, 1H), 5.89 (s, 1H), 4.29-4.21 methylthieno[2,3-b]pyrazine-6- (m, 1H), 4.17-4.14 (m, 1H), 3.83-3.78 carboxamide (m, 1H), 3.75-3.73 (m, 1H), 3.51-3.46 (m, 1H), 3.38 (s, 3H), 3.27-3.26 (m, 3H), 2.86-2.82 (m, 3H), 2.65 (s, 3H), 1.75 (br s, 2H). 148 7-amino-N-[(3R)-7-[(3R,4S)-3- 455 (DMSO-d6, 400 MHz) δ (ppm): 8.65 (s, ++++ ++ amino-4-methoxypyrrolidin-1- 1H), 7.74 (d, J = 7.2 Hz, 1H), 6.96 (s, yl]-3,4-dihydro-2H-1- 2H), 6.87 (d, J = 9.2 Hz, 1H), 6.08 (d, J = benzopyran-3-yl]-3- 6.4 Hz, 1H), 5.89 (s, 1H), 4.29-4.21 methylthieno[2,3-b]pyrazine-6- (m, 1H), 4.17-4.14 (m, 1H), 3.83-3.78 carboxamide (m, 1H), 3.75-3.73 (m, 1H), 3.49-3.48 (m, 1H), 3.34 (s, 3H), 3.32-3.27 (m, 1H), 3.27-3.24 (m, 2H), 2.85-2.82 (m, 3H), 265 (s, 3H), 1.70 (br s, 2H). 149 6-amino-N-[(3R)-7-[(3S,4R)-3- 460 (DMSO-d6, 400 MHz) δ (ppm): 7.39 (br ++++ ++ amino-4-methoxypyrrolidin-1- s, 1H), 7.12 (br s, 2H), 6.86 (d, J = 8.4 yl]-3,4-dihydro-2H-1- Hz, 1H), 6.07 (d, J = 10.8 Hz, 1H), 5.88 benzopyran-3-yl]-2- (s, 1H), 4.26-4.22 (m, 1H), 4.13-4.10 (m, methylthieno[2,3-d][1,3]thiazole- 1H), 3.78-3.73 (m, 2H), 3.50-3.46 (m, 5-carboxamide 1H), 3.33-3.31 (m, 3H), 3.29-3.27(m, 3H), 2.86-2.79 (m, 6H), 1.75 (br s, 2H). 150 6-amino-N-[(3R)-7-1(3R,4S)-3- 460 (DMSO-d6, 400 MHz) δ (ppm): 7.39 (br +++ ++ amino-4-methoxypyrrolidin-1- s, 1H), 7.12 (br s, 2H), 6.85 (d, J = 8.0 yl]-3,4-dihydro-2H-1- Hz, 1H), 6.07 (d, J = 10.4 Hz, 1H), 5.87 benzopyran-3-yl]-2- (s, 1H), 4.26-4.22 (m, 1H), 4.13-4.10 (m, methylthieno[2,3-d][1,3]thiazole- 1H), 3.76-3.73 (m, 2H), 3.50-3.46 (m, 5-carboxamide 1H), 3.33-3.31 (m, 3H), 3.29-3.27(m, 3H), 2.83-2.79 (m, 6H), 1.60 (br s, 2H). 151 3-amino-N-[(3R)-7-[(3S,4R)-3- 468 (DMSO-d6, 400 MHz) δ (ppm): 8.27 (d, ++++ ++ amino-4-ethoxypyrrolidin-1-yl]- J = 7.6 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 3,4-dihydro-2H-1-benzopyran-3- 6.86 (d, J = 8.0 Hz, 1H), 6.06 (d, J = 8.0 yl]-6-methylthieno[2,3- Hz, 1H), 5.87 (s, 1H), 4.27-4.25 (m, b]pyridine-2-carboxamide 2H),4.13-4.11 (m, 1H), 3.85-3.77(m, 2H), 3.49-3.42 (m, 3H), 3.38-3.28 (m, 2H), 3.21-3.18(m, 1H), 2.85-2.81 (m, 3H), 2.57 (s, 3H), 1.14-1.12(m, 3H). 152 3-amino-N-[(3R)-7-](3R,4S)-3- 468 (DMSO-d6, 400 MHz) δ (ppm): 8.29 (d, ++++ ++ amino-4-ethoxypyrrolidin-1-yl]- J = 8.4 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 3,4-dihydro-2H-1-benzopyran-3- 6.86 (d, J = 9.2 Hz, 1H), 6.07 (d, J = 7.2 yl]-6-methylthieno[2,3- Hz, 1H), 5.87 (s, 1H), 4.26 (br s, 2H), b]pyridine-2-carboxamide 4.14-4.11 (m, 1H), 3.84-3.77 (m, 2H), 3.46-3.44 (m, 2H), 3.35-3.28 (m, 2H), 3.21-3.19 (m, 1H), 2.85-2.81 (m, 3H), 2.58 (s, 3H), 1.15-1.12 (m, 3H). 153 N-[(3R)-7-[(4aS,7aR)- 466 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, +++ ++ octahydropyrrolo[3,4- J = 8.0 Hz, 1H), 7.47 (br s, 1H), 7.32 (d, b]morpholin-6-yl]-3,4-dihydro- J = 8.4 Hz, 1H), 7.21 (br s, 2H), 6.87 (d 2H-1-benzopyran-3-yl]-3-amino- J = 8.4 Hz, 1H), 6.09 (d, J = 10.4 Hz, 6-methylthieno[2,3-b]pyridine-2- 1H), 5.90 (s, 1H), 4.30-4.26 (m, 1H), carboxamide 4.15-4.13 (m, 1H), 3.97-3.95 (m, 1H), 3.82-3.77 (m, 1H), 3.68-3.66 (m, 1H), 3.49-3.37 (m, 3H), 3.31-3.29 (m, 1H), 3.15-3.11 (m, 2H), 2.96-2.82 (m, 3H), 2.59 (s, 3H), 2.55-2.50 (m, 1H). 154 N-[(3R)-7-[(4aR,7aS)- 466 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, +++ ++ octahydropyrrolo[3,4- J = 8.4 Hz, 1H), 7.47 (br s, 1H), 7.32 (d b]morpholin-6-yl]-3,4-dihydro- J = 8.0 Hz, 1H), 7.21 (br s, 2H), 6.87 (d, 2H-1-benzopyran-3-yl]-3-amino- J = 8.4 Hz, 1H), 6.09 (d, J = 8.4 Hz, 1H), 6-methylthieno[2,3-b]pyridine-2- 5.90 (s, 1H), 4.30-4.26 (m, 1H), 4.15- carboxamide 4.13 (m, 1H), 3.97-3.95 (m, 1H), 3.82- 3.77 (m, 1H), 3.68-3.66 (m, 1H), 3.49- 3.37 (m, 3H),3.15-3.10 (m, 2H), 2.95- 2.82 (m, 3H), 2.59 (s, 3H), 2.55-2.51 (m, 1H). 155 3-amino-N-[(3R)-7-[(2S)-2- 468 (DMSO-d6, 300 MHz) δ (ppm): 8.22-8.41 ++++ +++ (methoxymethyl)piperazin-1-yl]- (m, 2H), 7.52 (br d, J = 7.62 Hz, 1H), 7.31 3,4-dihydro-2H-1-benzopyran-3- (d, J = 8.21 Hz, 1H), 7.10-7.26 (m, 2H), yl]-6-methylthieno[2,3- 6.74-7.10 (m, 2H), 6.40-6.73 (m, 1H), b]pyridine-2-carboxamide 6.33 (s, 1H), 6.20-6.30 (m, 1H), 4.27 (br d, J = 7.92 Hz, 1H), 4.10-4.21 (m, 1H), 3.61-3.97 (m, 3H), 3.27-3.43 (m, 1H), 3.02-3.22 (m, 4H), 2.65-3.01 (m, 5H), 2.56-2.60 (m, 3H). 156 3-amino-N-[(3R)-7-[(21)-2- 468 (DMSO-d6, 300 MHz) δ (ppm): 8.26-8.48 +++ ++ (methoxymethyl)piperazin-1-yl]- (m, 1H), 8.13-8.25 (m, 4H), 7.53 (br d, 3,4-dihydro-2H-1-benzopyran-3- J = 7.62 Hz, 1H), 7.16-7.51 (m, 4H), 6.85- yl]-6-methylthieno[2,3- 7.16 (m, 1H), 6.43-6.70 (m, 1H), 6.29- b]pyridine-2-carboxamide 6.41 (m, 1H), 4.29 (br s, 1H), 4.04-4.24 (m, 2H), 3.76-4.01 (m, 3H), 3.51-3.75 (m, 2H), 3.28-3.50 (m, 3H), 2.94-3.21 (m, 6H), 2.79-2.94 (m, 3H), 2.57-2.74 (m, 5H), 2.43-2.48 (m, 1H), 1.31-1.46 (m, 1H). 157 3-amino-N-[(3R)-7-[(3R)-3- 468 1H NMR not taken. ++++ ++ (methoxymethyl)piperazin-1-yl]- 3,4-dihydro-2H-1-benzopyran-3- yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide 158 3-amino-N-[(3R)-7-[(3S)-3- 468 1H NMR not taken. +++ ++ (methoxymethyl)piperazin-1-yl]- 3,4-dihydro-2H-1-benzopyran-3- yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide 159 3-amino-N-[(3R)-5,6-difluoro-7- 474 (DMSO-d6, 400 MHz) δ(ppm): 7.65 (br + + (piperazin-1-yl)-3,4-dihydro-2H- s, 1H), 7.04 (s, 1H), 6.88 (br s, 2H), 6.28 1-benzopyran-3-yl]-4,6- (s, 1H), 4.36-4.28 (m, 1H), 4.18-4.16 (m, dimethylthieno[2,3-b]pyridine-2- 1H), 3.91-3.86 (m, 1H), 2.95-2.79 (m, carboxamide 10H), 2.73 (s, 3H), 2.51 (s, 3H). 160 3-amino-N-[(3S)-5,6-difluoro-7- 474 (DMSO-d6, 400 MHz) δ (ppm): 7.66 (br ++++ ++ (piperazin-1-yl)-3,4-dihydro-2H- s, 1H), 7.05 (s, 1H), 6.88 (br s, 2H), 6.27 1-benzopyran-3-yl]-4,6- (d, J = 6.8 Hz, 1H), 4.35-4.25 (m, 1H), dimethylthieno[2,3-b]pyridine-2- 4.18-4.16 (m, 1H), 3.90-3.86 (m, 1H), carboxamide 2.95-2.85 (m, 5H), 2.85-2.78 (m, 5H), 2.73 (s, 3H), 2.51 (s, 3H). 161 3-amino-N-[(3R)-7-[(3R,4R)-3- 468 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, ++++ ++ amino-4 J = 8.0 Hz, 1H), 7.49 (br s, 1H), 7.32 (d, (methoxymethyl)pyrrolidin-1-yl]- J = 8.4 Hz, 1H), 7.22 (br s, 2H), 6.87 3,4-dihydro-2H-1-benzopyran-3- J = 8.0 Hz, 1H), 6.10-6.07 (m, 1H), 5.88 yl]-6-methylthieno[2,3- (s, 1H), 4.31-4.26 (m, 1H), 4.16-4.13 (m, b]pyridine-2-carboxamide 1H), 3.81-3.77 (m, 1H), 3.60-3.55 (m, 2H), 3.41-3.33 (m, 2H), 3.28 (s, 3H), 3.25-3.21 (m, 1H), 3.09-3.05 (m, 1H), 2.96-2.93 (m, 1H), 2.85-2.82 (m, 2H), 2.59 (s, 3H), 2.52-2.41 (m, 1H), 1.53 (br s, 2H). 162 3-amino-N-[(3R)-7-[(3S,4S)-3- 468 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, ++++ +++ amino-4- J = 8.0 Hz, 1H), 7.47 (br s, 1H), 7.31 (d, (methoxymethyl)pyrrolidin-1-yl]- J = 8.4 Hz, 1H), 7.20 (br s, 2H), 6.86 (d, 3,4-dihydro-2H-1-benzopyran-3- J = 8.4 Hz, 1H), 6.09-6.07 (m, 1H), 5.88 yl]-6-methylthieno[2,3- (s, 1H), 4.31-4.26 (m, 1H), 4.15-4.12 (m, b]pyridine-2-carboxamide 1H), 3.82-3.77 (m, 1H), 3.60-3.54 (m, 2H), 3.41-3.35 (m, 2H), 3.28 (s, 3H), 3.25-3.21 (m, 1H), 3.09-3.05 (m, 1H), 2.96-2.93 (m, 1H), 2.85-2.81 (m, 2H), 2.59 (s, 3H), 2.52-2.41 (m, 1H), 1.53 (br s, 2H). 163 3-amino-N-[(3R)-7-[(3S,4R)-3- 468 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, J = ++++ ++ amino-4- 8.0 Hz, 1H), 7.49 (br s, 1H), 7.32 (d, J = (methoxymethyl)pyrrolidin-1-yl]- 8.4 Hz, 1H), 7.22 (br s, 2H), 6.86 (d, J = 3,4-dihydro-2H-1-benzopyran-3- 8.4 Hz, 1H), 6.10-6.07 (m, 1H), 5.88 yl]-6-methylthieno[2,3- (d, J = 2.0 Hz, 1H), 4.29-4.25 (m, 1H), b]pyridine-2-carboxamide 4.15-4.12 (m, 1H), 3.81-3.76 (m, 1H), 3.51-3.48 (m, 1H), 3.43-3.40 (m, 2H), 3.39-3.30 (m, 1H), 3.27 (s, 3H), 3.23- 3.18 (m, 1H), 3.00-2.95 (m, 1H), 2.89- 2.81 (m, 3H), 2.58 (s, 3H), 2.19-2.13 (m, 1H), 1.86 (br s, 2H). 164 3-amino-N-[(3R)-7-[(3R,4S)-3- 468 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, J = ++++ ++ amino-4- 8 Hz, 1H), 7.49 (br s, 1H), 7.32 (d, J = (methoxymethyl)pyrrolidin-1-yl]- 8.4 Hz, 1H), 7.22 (br s, 2H), 6.86 (d, J = 3,4-dihydro-2H-1-benzopyran-3- 8.4 Hz, 1H), 6.10-6.07 (m, 1H), 5.88 (d, yl]-6-methylthieno[2,3- J = 2.0 Hz, 1H), 4.30-4.25 (m, 1H), 4.15- b]pyridine-2-carboxamide 4.12 (m, 1H), 3.81-3.76 (m, 1H), 3.51- 3.48 (m, 1H), 3.43-3.39 (m, 2H), 3.35- 3.30 (m, 1H), 3.27 (s, 3H), 3.23-3.17 (m, 1H), 3.00-2.96 (m, 1H), 2.89-2.81 (m, 3H), 2.58 (s, 3H), 2.18-2.13 (m, 1H), 1.84 (br s, 2H). 165 N-[(3R)-7-[(3aR,6aR)- 450 (DMSO-d6 400 MHz) δ (ppm): 8.33 (d, ++++ +++ octahydropyrrolo[2,3-c]pyrrol-1- J = 8.0 Hz, 1H), 7.50 (br s, 1H), 7.32 (d yl]-3,4-dihydro-2H-1- J = 8.0 Hz, 1H), 7.22 (br s, 2H), 6.88 (d, benzopyran-3-yl]-3-amino-6- J = 8.4 Hz, 1H), 6.15 (dd, J = 8.4, 2.0 methylthieno[2,3-b]pyridine-2- Hz, 1H), 5.95 (s, 1H), 4.32-4.29 (m, 1H), carboxamide 4.16-4.13 (m, 1H), 3.89-3.85 (m, 1H), 3.77-3.82 (m, 1H), 3.40-3.32 (m, 1H), 3.05-3.03 (m, 1H), 2.86-2.64 (m, 7H), 2.59 (s, 3H), 2.04-2.02 (m, 1H), 1.75- 1.72 (m, 1H). 166 N-[(3R)-7-[(3aS,6aS)- 450 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, ++++ +++ octahydropyrrolo[2,3-c]pyrrol-1- J = 8.4 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), yl]-3,4-dihydro-2H-1- 7.32 (d, J = 8.4 Hz, 1H), 7.21 (s, 2H), benzopyran-3-yl]-3-amino-6- 6.88 (d, J = 8.4 Hz, 1H), 6.16-6.13 (m, methylthieno[2,3-b]pyridine-2- 1H), 5.95 (d, J = 2.4 Hz, 1H), 4.29-4.27 carboxamide (m, 1H), 4.16-4.13 (m, 1H), 3.88-3.86 (m, 1H), 3.85-3.77 (m, 1H), 3.38-3.36 (m, 1H), 3.05-3.03 (m, 1H), 2.86-2.64 (m, 7H), 2.59 (s, 3H), 2.08-2.03 (m, 1H), 1.75-1.72 (m, 1H). 167 3-amino-N-[(3R)-7-[(3R,4R)-3- 474 (DMSO-d6 300 MHz) δ (ppm): 8.33 (d, ++++ ++ amino-4- J = 8.4 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), (difluoromethyl)pyrrolidin-1-yl]- 7.32 (d, J = 8.4 Hz, 1H), 7.22 (br s, 2H), 3,4-dihydro-2H-1-benzopyran-3- 6.89 (d, J = 8.4 Hz, 1H), 6.38-6.12 (m yl]-6-methylthieno[2,3- 2H), 5.94 (s, 1H), 4.28-4.26 (m, 1H), b]pyridine-2-carboxamide 4.16-4.14 (m, 1H), 3.82-3.79 (m, 1H), 3.77-3.67 (m, 1H), 3.44-3.25 (m, 3H), 3.03-3.00 (m, 1H), 2.90-2.86 (m, 2H), 2.72-2.68 (m, 1H), 2.59 (s, 3H), 2.20 (br s, 2H). 168 3-amino-N-[(3R)-7-[(3S,4S)-3- 474 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, ++++ ++ amino-4- J = 8.4 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), (difluoromethyl)pyrrolidin-1-yl]- 7.32 (d, J = 8.4 Hz, 1H), 7.22 (br s, 2H), 3,4-dihydro-2H-1-benzopyran-3- 6.89 (d, J = 8.4 Hz, 1H), 6.38-6.12 (m, yl]-6-methylthieno[2,3- 2H), 5.93 (s, 1H), 4.28-4.26 (m, 1H), b]pyridine-2-carboxamide 4.16-4.14 (m, 1H), 3.82-3.80 (m, 1H), 3.77-3.67 (m, 1H), 3.44-3.27 (m, 3H), 3.03-3.00 (m, 1H), 2.86-2.82(m, 2H), 2.72-2.68 (m, 1H), 2.59(s, 3H), 1.80 (br s, 2H). 169 3-amino-N-[(3R)-5-fluoro-7- 426 (DMSO-d6, 400 MHz) δ (ppm): 8.20(d, J = ++ + (piperazin-1-yl)-3,4-dihydro-2H- 8.0 Hz, 1H), 7.96 (d, J = 7.6 Hz, 1H), 1-benzopyran-3-yl]-6- 7.23 (d, J = 8.0 Hz, 1H), 6.42 (d, J = methylfuro[2,3-b]pyridine-2- 13.6 Hz, 1H), 6.27-6.13 (m, 3H), 4.35- carboxamide 4.25 (m, 1H), 4.19-4.17 (m, 1H), 3.93- 3.88 (m, 1H), 3.07-2.91 (m, 4H), 2.89- 2.78 (m, 6H), 2.54 (s, 3H). 170 3-amino-N-[(3R)-7-{3,8- 452 (DMSO-d6 400 MHz) δ (ppm): 8.19 (d, ++ + diazabicyclo[3.2.1]octan-3-yl}-5- J = 7.6 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), fluoro-3,4-dihydro-2H-1- 7.22 (d, J = 8.0 Hz, 1H), 6.25-6.20 (m, benzopyran-3-yl]-6- 3H), 6.05 (s, 1H), 4.28 (br s, 1H), 4.18- methylfuro[2,3-b]pyridine-2- 4.12 (m, 1H), 3.92-3.90 (m, 1H), 3.48 (s, carboxamide 2H), 3.32-3.29 (m, 2H), 2.85-2.79 (m, 2H), 2.70-2.68 (m, 2H), 2.54 (s, 3H), 1.65 (s, 4H). 171 3-amino-N-[(2S)-6-{3,8- 432 (DMSO-d6 400 MHz) δ (ppm): 8.17 (d, + + diazabicyclo[3.2.1]octan-3-yl]- J = 8.0 Hz, 1H), 7.91 (br s, 1H), 7.22 (d, 1,2,3,4-tetrahydronaphthalen-2- J = 8.0 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), yl]-6-methylfuro[2,3-b]pyridine- 6.62 (d, J = 8.0 Hz, 1H), 6.51 (s, 1H), 2-carboxamide 6.11 (br s, 2H), 4.18-4.05 (m, 1H), 3.52- 3.51 (m, 2H), 3.32-3.31 (m, 2H), 2.85- 2.78 (m, 4H), 2.70-2.67 (m, 3H), 2.55 (s, 3H), 2.02-1.90 (m, 1H), 1.85-1.75 (m, 1H), 1.69-1.66 (m, 4H). 172 3-amino-N-[(3R)-7-{3,8- 470 (DMSO-d6, 400 MHz) δ (ppm): 8.20 (d, ++ + diazabicyclo[3.2.1]octan-3-yl}- J = 8.0 Hz, 1H), 8.05 (br s, 1H), 7.23 (d 5,8-difluoro-3,4-dihydro-2H-1- J = 7.6 Hz, 1H), 6.36-6.34 (m, 1H), 6.20 benzopyran-3-yl]-6- (br s, 2H), 4.33-4.27 (m, 1H), 4.26 (d, J = methylfuro[2,3-b]pyridine-2- 10.4 Hz, 1H), 4.02-3.97 (m, 1H), 3.39- carboxamide 3.32 (s, 2H), 3.09-3.06 (m, 2H), 2.93- 2.86 (m, 2H), 2.84-2.78 (m, 2H), 2.54 (s, 3H), 2.34-2.33 (m, 1H), 1.81-1.78 (m, 2H), 1.65-1.64 (m, 2H). 173 3-amino-N-[(3R)-7-{3,8- 451 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, +++ ++ diazabicyclo[3.2.1]octan-3-yl]- J = 8.4 Hz, 1H), 7.57 (d, J = 7.2 Hz, 1H), 2H,3H,4H-pyrano[2,3-b]pyridin- 7.33-7.23 (m, 4H), 6.24 (d, J = 8.4 Hz, 3-yl]-6-methylthieno[2,3- 1H), 4.33-4.24 (m, 1H), 4.22-4.19 (m, b]pyridine-2-carboxamide 1H), 3.98-3.93 (m, 1H), 3.70-3.66 (m, 1H), 3.47-3.45 (m, 2H), 2.88-2.76 (m, 4H), 2.59 (s, 3H), 2.51-2.42 (m, 1H), 1.65-1.55 (m, 4H). 174 7-amino-N-[(3R)-7-[(3S,4S)-3- 498 (DMSO-d6, 400 MHz) δ (ppm): 8.66 (s, ++ + amino-4-methoxypyrrolidin-1- 1H), 7.90 (d, J = 6.8 Hz, 1H), 7.00 (br s, yl]-8-cyano-5-fluoro-3,4-dihydro- 2H), 6.20 (d, J = 12.8 Hz, 1H), 4.35-4.33 2H-1-benzopyran-3-yl]-3- (m, 2H), 4.08-4.03 (m, 1H), 3.83-3.79 methylthieno[2,3-b]pyrazine-6- (m, 1H), 3.71-3.64(m, 2H), 3.47-3.46(m, carboxamide 1H), 3.40-3.37 (m, 1H), 3.31 (s, 3H), 3.24-3.22 (m, 1H), 2.90-2.84 (m, 1H), 2.76-2.70 (m, 1H), 2.66 (s, 3H), 1.75 (br s, 2H). 175 3-amino-N-[(3R)-7-[(3S,4S)-3- 497 (DMSO-d6, 400 MHz) δ (ppm): 8.32 (d, +++ + amino-4-methoxypyrrolidin-1- J = 8.4 Hz, 1H), 7.65 (d, J = 6.8 Hz, 1H), yl]-8-cyano-5-fluoro-3,4-dihydro- 7.32 (d, J = 8.4 Hz, 1H), 7.24 (br s, 2H), 2H-1-benzopyran-3-yl]-6- 6.18 (d, J = 12.8 Hz, 1H), 4.34-4.31 (m, methylthieno[2,3-b]pyridine-2- 2H), 4.06-4.01 (m, 1H), 3.82-3.80 (m, carboxamide 1H) 3.70-3.64 (m, 2H), 3.47-3.37(m, 2H), 3.33 (s, 3H), 3.24-3.21(m, 1H), 2.87-2.83 (m, 1H), 2.75-2.71 (m, 1H), 2.59 (s, 3H), 1.78 (br s, 2H). 176 7-amino-N-[(3R)-7-[(3S,4S)-3- 480 (DMSO-d6, 400 MHz) δ (ppm): 8.66 (s, ++++ +++ amino-4-methoxypyrrolidin-1- 1H), 7.83 (br s, 1H), 7.31 (s, 1H), 6.99 yl]-6-cyano-3,4-dihydro-2H-1- (br s, 2H), 6.11 (s, 1H), 4.32-4.24 (m, benzopyran-3-yl]-3- 2H), 3.95-3.90 (m, 1H), 3.80-3.76 (m, methylthieno[2,3-b]pyrazine-6- 1H), 3.66-3.63 (m, 2H), 3.46-3.45 (m, carboxamide 1H), 3.37-3.34 (m, 1H), 3.32 (s, 3H), 3.19-3.16 (m, 1H), 2.94-2.81 (m, 2H), 2.68 (s, 3H), 1.78 (br s, 2H). 177 3-amino-N-[(3R)-7-[(3S,4S)-3- 479 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, ++++ +++ amino-4-methoxypyrrolidin-1- J = 8.0 Hz, 1H), 7.58 (br s 1H), 7.33- yl]-6-cyano-3-4-dihydro-2H-1- 7.31 (m, 2H), 7.22 (br s, 2H), 6.10 (s, benzopyran-3-yl]-6- 2H), 4.32-4.22 (m, 2H), 3.92-3.88 (m, methylthieno[2,3-b]pyridine-2- 1H), 3.79-3.76 (m, 1H), 3.67-3.63 (m, carboxamide 2H), 3.45 (s, 1H), 3.37-3.33 (m, 1H), 3.32 (s, 3H), 3.18-3.16 (m, 1H), 2.91- 2.80 (m, 2H), 2.59 (s, 3H), 1.77 (br s, 2H). 178 3-amino-N-[(2S)-6-[(3S,4S)-3- 477 (DMSO-d6 400 MHz) δ (ppm): 8.31 (d, ++++ ++ amino-4-methoxypyrrolidin-1- J = 8.4 Hz, 1H), 7.58(d, J = 7.6 Hz, 1H), yl]-5-cyano-1,2,3,4- 7.31 (d, J = 8.4 Hz, 1H), 7.15-7.13 (m, tetrahydronaphthalen-2-yl]-6- 3H), 6.61 (d, J = 8.8 Hz, 1H),4.14-4.08 methylthieno[2,3-b]pyridine-2- (m, 1H), 3.86-3.82 (m, 1H), 3.73-3.71 carboxamide (m, 1H), 3.65-3.64 (m, 1H), 3.46-3.45 (m, 1H), 3.40-3.38 (m, 1H), 3.31 (s, 3H), 3.22-3.20 (m, 1H), 3.05-2.97 (m, 1H), 2.88-2.84 (m, 2H), 2.78-2.68 (m, 1H), 2.59 (s, 3H), 2.09-2.01 (m, 1H), 1.85- 1.74 (m, 3H). 179 3-amino-N-[(3R)-7-[(3S,4S)-3- 455 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, ++++ amino-4-methoxypyrrolidin-1- J = 8.4 Hz, 1H), 7.78 (s, 1H), 7.56 (d, J = yl]-2H,3H,4H-pyrano[3,2- 7.6 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), c]pyridin-3-yl]-6- 7.22 (br s, 2H), 5.78 (s,1H), 4.32-4.27 methylthieno[2,3-b]pyridine-2- (m, 1H), 4.25-4.19 (m, 1H), 3.91-3.86 carboxamide (m, 1H), 3.61-3.55 (m, 2H), 3.44-3.40 (m, 2H), 3.33-3.30 (m, 1H), 3.29 (s, 3H), 3.11-3.08 (m, 1H), 2.85-2.81 (m, 2H), 2.59 (s, 3H), 1.74-1.71 (m, 2H). 180 3-amino-N-[(3R)-7-[(3S,4S)-3- 469 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, ++++ amino-4-ethoxypyrrolidin-1-yl]- J = 8.4 Hz, 1H), 7.78 (s, 1H), 7.56 (d, J = 2H,3H,4H-pyrano[3,2-c]pyridin- 7.6 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 3-yl]-6-methylthieno[2,3- 7.22 (br s, 2H), 5.77 (s, 1H), 4.32-4.23 b]pyridine-2-carboxamide (m, 1H), 4.22-4.20 (m, 1H), 3.91-3.89 (m, 1H), 3.71-3.69 (m, 1H), (s, 1H), 3.62-3.57 (m, 1H), 3.52 (t, J = 6.8 Hz, 2H), 3.49-3.32 (m, 1H), 3.31-3.27 (m, 1H), 3.09-3.07 (m, 1H), 2.85-2.81 (m, 2H), 2.58 (s, 3H), 1.74-1.69 (m, 2H), 1.11 (t, J = 7.2 Hz, 3H). 181 7-amino-N-[(3R)-7-[(3S,4S)-3- 456 (DMSO-d6 400 MHz) δ (ppm): 8.66 (s, ++ + amino-4-methoxypyrrolidin-1- 1H), 7.78 (d, J = 7.2 Hz, 1H), 7.26 (d, J = yl]-2H,3H,4H-pyrano[2,3- 8.0 Hz, 1H), 6.97 (br s, 2H), 6.02 (d, J = b]pyridin-3-yl]-3- 8.4 Hz, 1H), 4.32-4.28 (m, 1H), 4.24- methylthieno[2,3-b]pyrazine-6- 4.21 (m, 1H), 4.00-3.95 (m, 1H), 3.62- carboxamide 3.55 (m, 2H), 3.43-3.40 (m, 2H) 3.32- 3.29 (m, 4H), 3.11-3.08 (m, 1H), 2.85- 2.83(m, 2H), 2.65 (s, 3H), 1.77 (brs, 2H). 182 7-amino-N-[(3R)-7-[(3S,4S)-3- 470 (DMSO-d6 400 MHz) δ (ppm): 8.66 (s, ++ + amino-4-ethoxypyrrolidin-1-yl]- 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.26 (d, J = 2H,3H,4H-pyrano[2,3-b]pyridin- 8.4 Hz, 1H), 6.97 (br, 2H), 6.02 (d, J = 3-yl]-3-methylthieno[2,3- 8.4 Hz, 1H), 4.32-4.26 (m, 1H), 4.24- b]pyrazine-6-carboxamide 4.21 (m, 1H), 4.00-3.95 (m, 1H), 3.72- 3.70(m, 1H), 3.61-3.57 (m, 1H), 3.54- 3.52 (m, 2H), 3.51-3.41 (m, 2H), 3.29- 3.26 (m, 1H), 3.10-3.08 (m, 1H), 2.85- 2.83 (m, 2H), 2.66 (s, 3H), 1.79 (brs, 2H), 1.15-1.08 (m, 3H). 183 3-amino-N-[(6S)-2-[(3S,4S)-3- 471 (DMSO-d6, 400 MHz) δ (ppm): 8.31 (d, +++ + amino-4-methoxypyrrolidin-1- J = 8.4 Hz, 1H), 7.58 (br s, 1H), 7.31 (d, yl]-3-fluoro-5,6,7,8- J = 8.4 Hz, 1H), 7.16-7.12 (m, 3H), 4.15- tetrahydroquinolin-6-yl]-6- 4.12 (m, 1H), 3.80-3.77 (m, 1H), 3.66- methylthieno[2,3-b]pyridine-2- 3.58 (m, 2H), 3.48-3.45 (m, 1H), 3.40- carboxamide 3.39 (m, 1H), 3.32-3.26 (m, 4H), 2.84- 2.66 (m, 4H), 2.59 (s, 3H), 2.01-1.90 (m, 1H), 1.89-1.82 (m, 1H), 1.74 (br s, 2H). 184 N-[(3R)-7-[(4aR, 7aS)- 466 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, ++++ +++ octahydropyrrolo[3,4- J = 8.0 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), b]morpholin-4-yl]-3,4-dihydro- 7.32 (d,J = 8.4 Hz, 1H), 7.22 (s, 2H), 2H-1-benzopyran-3-yl]-3-amino- 6.92 (d, J = 8.8 Hz, 1H), 6.52-6.49 (m, 6-methylthieno[2,3-b]pyridine-2- 1H), 6.29 (s,1H), 4.29 (br s, 1H), 4.17- carboxamide 4.14 (m, 1H), 3.97-3.90 (m, 3H), 3.83- 3.78 (m, 1H), 3.56-3.53 (m, 1H), 3.22- 3.11 (m, 2H), 2.90-2.73 (m, 5H), 2.59 (s, 3H). 185 N-[(3R)-7-[(4aS,7aR)- 466 (DMSO-d6 400 MHz) δ (ppm): 8.33 (d, ++++ +++ octahydropyrrolo[3,4- J = 8.0 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), b]morpholin-4-yl]-3,4-dihydro- 7.32 (d, J = 8.4 Hz, 1H), 7.22 (s, 2H), 2H-1-benzopyran-3-yl]-3-amino- 6.92 (d, J = 8.8 Hz, 1H), 6.51-6.49 (m, 6-methylthieno[2,3-b]pyridine-2- 1H), 6.30 (s,1H), 4.31-4.27 (br s, 1H), carboxamide 4.17-4.15 (m, 1H), 3.97-3.91 (m, 2H), 3.83-3.78 (m, 1H), 3.59-3.54 (m, 1H), 3.26-3.12 (m, 2H), 2.91-2.78 (m, 5H), 2.59 (s, 3H). 186 3-amino-N-[(6S)-2-[(3S,4S)-3- 454 (DMSO-d6, 400 MHz) δ (ppm): 8.31 (d, + amino-4-methoxypyrrolidin-1- J = 8.4 Hz, 1H), 8.06 (s, 1H), 7.62 (br s, yl]-5,6,7,8-tetrahydroquinazolin- 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.17 (br s, 6-yl]-6-methylthieno[2,3- 2H), 4.16-4.11 (m, 1H), 3.69-3.62 (m, b]pyridine-2-carboxamide 2H), 3.53-3.43 (m, 3H), 3.29-3.27 (m, 4H), 2.84-2.73 (m, 3H), 2.68-2.59 (m, 4H), 2.01-1.98 (m, 1H), 1.90-1.80 (m, 1H), 1.73 (br s, 2H). 187 3-amino-N-[(6R)-2-[(3S,4S)-3- 454 (DMSO-d6, 400 MHz) δ (ppm): 8.31 (d, ++ amino-4-methoxypyrrolidin-1- J = 8.0 Hz, 1H), 8.06 (s, 1H), 7.62 (br s, yl]-5,6,7,8-tetrahydroquinazolin- 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.17 (br s, 6-yl]-6-methylthieno[2,3- 2H), 4.15-4.11 (m, 1H), 3.69-3.62 (m, b]pyridine-2-carboxamide 2H), 3.54-3.43 (m, 3H), 3.29-3.27 (m, 4H), 2.84-2.73 (m, 3H), 2.68-2.59 (m, 4H), 2.01-1.98 (m, 1H), 1.90-1.73 (m, 3H). 188 N-[(2S)-6-[(3S,4S)-3-amino-4- 434 (DMSO-d6, 400 MHz) δ (ppm): 8.29 (s, ++ + methoxypyrrolidin-1-yl]-1,2,3,4- 1H), 8.04 (d, J = 7.2 Hz, 1H), 7.87 (s, tetrahydronaphthalen-2-yl]- 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.52 (s, 5H,6H,6aH,7H,7aH- 1H), 6.31 (d, J = 8.4 Hz, 1H), 6.23 (s, cyclopropa[c]1,8-naphthyridine- 1H), 4.11-4.03 (m, 1H), 3.64-3.62 (m, 2-carboxamide 1H), 3.53-3.49 (m, 1H), 3.41-3.35 (m, 5H), 3.32 (s, 3H), 3.14-3.11 (m, 1H), 2.92-2.79 (m, 3H), 2.67-2.64 (m, 1H), 1.98-1.93 (m, 2H), 1.82-1.64 (m, 4H), 0.97-0.93 (m, 2H). 189 (6aS,7aR)-N-[(2S)-6-[(3S,4S)-3- 434 (DMSO-d6, 400 MHz) δ (ppm): 8.29 (s, ++ + amino-4-methoxypyrrolidin-1- 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.86 (s, yl]-1,2,3,4- 1H), 6.86 (d, J = 8.0 Hz, 1H), 6.53 (s, tetrahydronaphthalen-2-yl]- 1H), 6.31 (d, J = 8.0 Hz, 1H), 6.23 (s, 5H,6H,6aH,7H,7aH- 1H), 4.11-4.03 (m, 1H), 3.65-3.63 (m, cyclopropa[c]1,8-naphthyridine- 1H), 3.52-3.49 (m, 1H), 3.42-3.34 (m, 2-carboxamide 4H), 3.32 (s, 3H), 3.14-3.11 (m, 1H), 2.92-2.78 (m, 4H), 2.67-2.63 (m, 1H), 2.06-1.93 (m, 4H), 1.74-1.64 (m, 4H), 0.96-0.91 (m, 2H). 190 (6aR,7aS)-N-[(2S)-6-[(3S,4S)-3- 434 (DMSO-d6, 400 MHz) δ (ppm): 8.29 (s, + + amino-4-methoxypyrrolidin-1- 1H), 8.05 (d, = 7.6 Hz, 1H), 7.86 (s, yl]-1,2,3,4- 1H), 6.86 (d, J = 8.4 Hz, 1H),6.53 (s, tetrahydronaphthalen-2-yl]- 1H), 6.31 (dd, J = 8.0, 2.0 Hz, 1H), 6.23 5H,6H,6aH,7H,7aH- (s, 1H), 4.11-4.03 (m, 1H), 3.65-3.63 (m, cyclopropa[c]1,8-naphthyridine- 1H), 3.52-3.49 (m, 1H), 3.42-3.34 (m, 2-carboxamide 4H), 3.32 (s, 3H), 3.14-3.11 (m, 1H), 2.92-2.78 (m, 4H), 2.67-2.63 (m, 1H), 2.04-1.93 (m, 4H), 1.74-1.64 (m, 4H), 0.96-0.92 (m, 2H). 191 (6aS,7aR)-N-[(2S)-6-{3,8- 448 (DMSO-d6, 400 MHz) δ (ppm): 8.29 (s, + + diazabicyclo[3.2.1]octan-3-yl}-8- 1H), 8.10 (br s, 1H), 7.86 (s, 1H), 6.55 fluoro-1,2,3,4- (s, 1 H), 6.42 (d, J = 12.4 Hz, 1H), 6.36 tetrahydronaphthalen-2-yl]- (br s, 1 H), 4.13-4.07 (m, 1H), 3.48-3.46 5H,6H,6aH,7H,7aH- (m, 2H), 3.39-3.37 (m, 4H), 2.94-2.89 cyclopropa[c]1,8-naphthyridine- (m, 1H), 2.82-2.76 (m, 2H), 2.73-2.68 2-carboxamide (m, 2H), 2.50-2.35 (m, 1H), 1.98-1.95 (m, 2H), 1.76-1.62 (m, 6H), 0.96-0.91 (m, 2H). 192 (6aR,7aS)-N-[(2S)-6-{3,8- 448 (DMSO-d6, 400 MHz) δ (ppm): 8.29 (s, +++ +++ diazabicyclo[3.2.1]octan-3-yl}-8- 1H), 8.09 (br s, 1H), 7.86 (s, 1H), 6.55 fluoro-1,2,3,4- (s, 1 H), 6.42 (d, J = 13.6 Hz, 1H), 6.36 tetrahydronaphthalen-2-yl]- (br s, 1 H), 4.13-4.07 (m, 1H), 3.48-3.46 5H,6H,6aH,7H,7aH- (m, 2H), 3.39-3.37 (m, 2H), 3.33-3.20 cyclopropa[c]1,8-naphthyridine- (m, 2H), 2.94-2.89 (m, 1H), 2.82-2.76 2-carboxamide (m, 2H), 2.73-2.68 (m, 2H), 2.50-2.35 (m, 1H), 1.98-1.95 (m, 2H), 1.76-1.62 (m, 6H), 0.97-0.91 (m, 2H). 193 (6aS,7aR)-N-[(2R)-6-{3,8- 448 (DMSO-d6, 400 MHz) δ (ppm): 8.29 (s, ++ + diazabicyclo[3.2.1]octan-3-yl}-8- 1H), 8.09 (br s, 1H), 7.86 (s, 1H), 6.54 fluoro-1,2,3,4- (s, 1 H), 6.42 (d, J = 13.6 Hz, 1H), 6.36 tetrahydronaphthalen-2-yl]- (br s, 1 H), 4.13-4.07 (m, 1H), 3.48-3.43 5H,6H,6aH,7H,7aH- (m, 2H), 3.41-3.38 (m, 2H), 3.34-3.32 cyclopropa[c]1,8-naphthyridine- (m, 2H), 2.94-2.89 (m, 1H), 2.81-2.75 2-carboxamide (m, 2H), 2.71-2.64 (m, 2H), 2.50-2.33 (m, 1H), 1.98-1.92 (m, 2H), 1.74-1.66 (m, 6H), 0.97-0.90 (m, 2H). 194 (6aR,7aS)-N-[(2R)-6-{3,8- 448 (DMSO-d6, 400 MHz) δ (ppm): 8.29 (s, ++ ++ diazabicyclo[3.2.1]octan-3-yl}-8- 1H), 8.09 (br s, 1H), 7.86 (s, 1H), 6.55 fluoro-1,2,3,4- (s, 1 H), 6.42 (d, J = 12.8 Hz, 1H), 6.37 tetrahydronaphthalen-2-yl]- (br s, 1 H), 4.13-4.07 (m, 1H), 3.48-3.46 5H,6H,6aH,7H,7aH- (m, 2H), 3.39-3.37 (m, 2H), 3.33-3.20 cyclopropa[c]1,8-naphthyridine- (m, 2H), 2.94-2.89 (m, 1H), 2.82-2.76 2-carboxamide (m, 2H), 2.73-2.68 (m, 2H), 2.50-2.35 (m, 1H), 1.98-1.93 (m, 2H), 1.76-1.63 (m, 6H), 0.96-0.90 (m, 2H). 195 (6aS,7aR)-N-[(2S)-5-cyano-6- 473 (DMSO-d6, 400 MHz) δ (ppm): 8.28 (s, ++++ +++ {3,8-diazabicyclo[3.2.1]octan-3- 1H), 8.13 (br s, 1H), 7.85 (s, 1H), 6.79 yl}-8-fluoro-1,2,3,4- (d, J = 12.0 Hz, 1H), 6.56 (br s, 1H), tetrahydronaphthalen-2-yl]- 4.18-4.11 (m, 1H), 3.45-3.43 (m, 2H), 5H,6H,6aH,7H,7aH- 3.38-3.37 (m, 2H), 3.26-3.23 (m, 2H), cyclopropa[c]1,8-naphthyridine- 3.03-2.88 (m, 5H), 2.57-2.51 (m, 1H), 2-carboxamide 2.05-2.03 (m, 1H), 1.98-1.90 (m, 3H), 1.81-1.72 (m, 2H), 1.66-1.64 (m, 2H), 0.96-0.91 (m, 2H). 196 (6aR,7aS)-N-[(2S)-5-cyano-6- 473 (DMSO-d6, 400 MHz) δ (ppm): 8.28 (s, + + {3,8-diazabicyclo[3.2.1]octan-3- 1H), 8.13 (br s, 1H), 7.86 (s, 1H), 6.79 yl}-8-fluoro-1,2,3,4- (d, J = 12.0 Hz, 1H), 6.56 (br s, 1H), tetrahydronaphthalen-2-yl]- 4.18-4.12 (m, 1H), 3.45-3.43 (m, 2H), 5H,6H,6aH,7H,7aH- 3.38-3.37 (m, 2H), 3.26-3.23 (m, 2H), cyclopropa[c]1,8-naphthyridine- 3.03-2.88 (m, 5H), 2.68 (br s, 1H), 2.57- 2-carboxamide 2.51 (m, 1H), 2.07-2.03 (m, 1H), 1.98- 1.90 (m, 3H), 1.81-1.72 (m, 2H), 1.66- 1.64 (m, 2H), 0.95-0.91 (m, 2H). 197 (6aS,7aR)-N-[(2R)-5-cyano-6- 473 (DMSO-d6, 400 MHz) δ (ppm): 8.29 (s, + + {3,8-diazabicyclo[3.2.1]octan-3- 1H), 8.13 (br s, 1H), 7.86 (s, 1H), 6.79 yl}-8-fluoro-1,2,3,4- (d, J = 11.6 Hz, 1H), 6.57 (br s, 1H), tetrahydronaphthalen-2-yl]- 4.18-4.11 (m, 1H), 3.45-3.43 (m, 2H), 5H,6H,6aH,7H,7aH- 3.38-3.37 (m, 2H), 3.26-3.23 (m, 2H), cyclopropa[c]1,8-naphthyridine- 3.03-2.88 (m, 5H), 2.57-2.51 (m, 1H), 2-carboxamide 2.05-2.03 (m, 1H), 1.98-1.90 (m, 3H), 1.81-1.72 (m, 2H), 1.66-1.64 (m, 2H), 0.95-0.85 (m, 2H). 198 (6aR,7aS)-N-[(2R)-5-cyano-6- 473 (DMSO-d6, 400 MHz) δ (ppm): 8.28 (s, ++ ++ {3,8-diazabicyclo[3.2.1]octan-3- 1H), 8.13 (br s, 1H), 7.86 (s, 1H), 6.79 yl}-8-fluoro-1,2,3,4- (d, J = 12.0 Hz, 1H), 6.56 (br s, 1H), tetrahydronaphthalen-2-yl]- 4.18-4.11 (m, 1H), 3.46-3.43 (m, 2H), 5H,6H,6aH,7H,7aH- 3.39-3.37 (m, 2H), 3.27-3.24 (m, 2H), cyclopropa[c]1,8-naphthyridine- 3.05-2.89 (m, 5H), 2.57-2.51 (m, 1H), 2-carboxamide 2.05-2.03 (m, 1H), 1.98-1.92 (m, 3H), 1.87-1.81 (m, 2H), 1.79-1.76 (m, 2H), 0.96-0.91 (m, 2H). 199 7-amino-N-[(3R)-7-[(3S,4S)-3- 498 (DMSO-d6, 400 MHz) δ (ppm): 8.66 (s, ++++ +++ amino-4-methoxypyrrolidin-1- 1H), 7.86 (d, J = 6.4 Hz, 1H), 6.99 (br s, yl]-6-cyano-5-fluoro-3,4-dihydro- 2H), 5.97 (s, 1H), 4.32-4.24 (m, 2H), 2H-1-benzopyran-3-yl]-3- 4.04-3.99 (m, 1H), 3.81-3.78 (m, 1H), methylthieno[2,3-b]pyrazine-6- 3.65 (br s, 2H), 3.47 (s, 1H), 3.40- carboxamide 3.37 (m, 1H), 3.33 (s, 3H), 3.23-3.20 (m, 1H), 2.95-2.91 (m, 1H), 2.79-2.73 (m, 1H), 2.65 (s, 3H), 1.90-1.79 (br s, 2H). 200 3-amino-N-[(3R)-7-(3S,4S)-3- 497 (DMSO-d6, 400 MHz) δ (ppm): 8.35 (d, ++++ +++ amino-4-methoxypyrrolidin-1- J = 8.4 Hz, 1H), 7.63 (d, J = 6.8 Hz, 1H), yl]-6-cyano-5-fluoro-3 4-dihydro- 7.32 (d, J = 8.4 Hz, 1H), 7.23 (br s, 2H), 2H-1-benzopyran-3-yl]-6- 5.98 (s, 1H), 4.33-4.24(m, 2H), 4.02-3.99 methylthieno[2,3-b]pyridine-2- (m, 1H), 3.81-3.78 (m, 1H), 3.66-3.64 carboxamide (m, 2H), 3.48-3.37(m, 2H), 3.33 (s, 3H), 3.23-3.21(m, 1H), 2.94-2.87(m, 1H), 2.79-2.72 (m, 1H), 2.59 (s, 3H), 1.87- 1.75(br s, 2H). 201 3-amino-N-[(2S)-6-[(3S,4S)-3- 477 (DMSO-d6, 400 MHz) δ (ppm): 8.30 (d, ++++ ++ amino-4-methoxypyrrolidin-1- J = 8.0 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), yl]-7-cyano-1,2,3,4- 7.31 (d, J = 8.0 Hz, 1H), 7.26 (s, 1H), tetrahydronaphthalen-2-yl]-6- 7.16 (br s, 2H), 6.51 (s, 1H), 4.13-4.08 methylthieno[2,3-b]pyridine-2- (m, 1H), 3.83-3.79 (m, 1H), 3.70-3.66 carboxamide (m, 2H), 3.47-3.46 (m, 1H), 3.38-3.35 (m, 1H), 3.30 (s, 3H), 3.19-3.17 (m, 1H), 2.91-2.82 (m, 3H), 2.72-2.66 (m, 1H), 2.59 (s, 3H), 1.98-1.95 (m, 1H), 1.80-1.71 (m, 3H). 202 3-amino-N-[(3R)-7-[(3S,4S)-3- 482 (DMSO-d6, 400 MHz) δ (ppm): 8.32 (d, ++++ ++ amino-4-(propan-2- J = 8.4 Hz, 1H), 7.48 (d, J = 7.2 Hz, 1H), yloxy)pyrrolidin-1-yl]-3,4- 7.32 (d, J = 8.4 Hz, 1H),7.21 (br s, 2 H), dihydro-2H-1-benzopyran-3-yl] 6.86 (d, J = 8.4 Hz, 1H), 6.09 (d, J = 8.4 6-methylthieno[2,3-b]pyridine-2- Hz, 1H), 5.90 (s, 1H), 4.31-4.24 (m, 1H), carboxamide 4.15-4.13 (m, 1H), 3.79-3.70 (m, 3H), 3.54-3.50 (m, 1H), 3.38-3.32 (m, 3H), 3.02-2.99 (m, 1H), 2.88-2.79 (m, 3H), 2.59 (s, 3H),1.69 (br s, 2H), 1.13-1.08 (m, 3H). 203 3-amino-N-[(6S)-2-[(3S,4S)-3- 471 (DMSO-d6, 400 MHz) δ (ppm): 8.29 (d, J = +++ + amino-4-methoxypyrrolidin-1- 10.4 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), yl]-5,6,7,8-tetrahydroquinolin-6- 7.19 (d, J = 8.4 Hz, 1H), 7.12 (br s, 2H), yl}-5-fluoro-6-methylthieno[2,3- 6.23 (d, J = 8.4 Hz, 1H), 4.19-4.08 (m, b]pyridine-2-carboxamide 1H), 3.62-3.59 (m, 2H), 3.48-3.43 (m, 2H), 3.36-3.35 (m, 1H), 3.32 (s, 3H), 3.13-3.11 (m, 1H), 2.82-2.68 (m, 4H), 2.57 (s, 3H), 2.01-1.99 (m, 1H), 1.90- 1.80 (m, 1H), 1.70 (br s, 2H). 204 3-amino-5-fluoro-6-methyl-N- 441 (DMSO-d6, 400 MHz) δ (ppm): 8.30 (d, J = ++++ ++ [(6S)-2-(piperazin-1-yl)-5,6,7,8- 10.8 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), tetrahydroquinolin-6- 7.24 (d, J = 8.0 Hz, 1H), 7.12 (br s, 2H), yl]thieno[2,3-b]pyridine-2- 6.59 (d, J = 8.8 Hz, 1H), 4.15-4.11 (m, carboxamide 1H), 3.34-3.31 (m, 4H), 2.84-2.68 (m, 8H), 2.56 (s, 3H), 2.07-1.98 (m, 1H), 1.90-1.85 (m, 1H). 205 3-amino-6-methyl-N-[(6S,8S)-8- 437 (DMSO-d6 400 MHz) δ (ppm): 8.31 (d, methyl-2-(piperazin-1-yl)- J = 8.0 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 5,6,7,8-tetrahydroquinolin-6- 7.31 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 8.4 yl]thieno[2,3-b]pyridine-2- Hz, 1H), 7.17 (s, 2H), 6.59 (d, J = 8.0 ++ + carboxamide Hz, 1H), 4.16-4.11 (m, 1H), 3.36-3.33 (m, 4H), 2.84-2.73 (m, 7H), 2.60 (s, 3H),2.17-2.11 (m, 1H), 1.64-1.55 (m, 1H), 1.32 (d, J = 6.4 Hz, 3H). 206 3-amino-6-methyl-N-[(6R,8S)-8- 437 (DMSO-d6 400 MHz) δ (ppm): 8.33 (d, +++ + methyl-2-(piperazin-1-yl)- J = 7.2 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 5,6,7,8-tetrahydroquinolin-6- 7.31 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 yl]thieno[2,3-b]pyridine-2- Hz, 1H), 7.16 (s, 2H), 6.59 (d, J = 8.0 carboxamide Hz, 1H),4.34-4.30 (m, 1H), 3.34-3.32 (m, 4H), 2.93-2.65 (m, 7H), 2.59 (s, 3H), 2.09-2.02 (m, 1H), 1.79-1.76 (m, 1H), 1.34 (d, J = 4.4 Hz, 3H). 207 3-amino-6-methyl-N-[(6S,8R)-8- 437 (DMSO-d6 400 MHz) δ (ppm): 8.31 (d, ++ + methyl-2-(piperazin-1-yl)- J = 8.4 Hz, 1H), 7.54 (d, J = 7.2 Hz, 1H), 5,6,7,8-tetrahydroquinolin-6- 7.31 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 8.4 yl]thieno[2,3-b]pyridine-2- Hz, 1H), 7.16 (s, 2H), 6.59 (d, J = 8.0 carboxamide Hz, 1H), 4.32 (br s, 1H), 3.34-3.32 (m 4H), 2.92-2.69(m, 7H), 2.59 (s, 3H), 2.09-2.02(m, 1H), 1.79-1.76 (m, 1H), 1.29 (d, J = 6.8 Hz, 3H). 208 3-amino-6-methyl-N-[(6R,8R)-8- 437 (DMSO-d6 400 MHz) δ (ppm): 8.31 (d, ++++ ++ methyl-2-(piperazin-1-yl)- J = 8.0 Hz, 1H), 7.59 (d, J = 7.2 Hz, 1H), 5,6,7,8-tetrahydroquinolin-6- 7.31 (d, J = 8.4 Hz, 1H), 7.23 (d, J = yl]thieno[2,3-b]pyridine-2- 8.4 Hz, 1H), 7.16 (s, 2H), 6.58 (d, J = 8.8 carboxamide Hz, 1H), 4.17-4.14 (m, 1H), 3.35-3.33 (m, 4H), 2.86-2.72 (m, 7H), 2.59 (s, 3H), 2.13-2.11(m, 1H), 1.63-1.54 (m, 1H), 1.31 (d, J = 6.8 Hz, 3H). 209 3-amino-6-methyl-N-[(3R)-7-{3- 466 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, ++++ ++++ oxa-7,9- J = 8.4 Hz, 1H), 7.52 (br s, 1H), 7.32 (d, diazabicyclo[3.3.1]nonan-9-yl}- J = 8.0 Hz, 1H), 7.22 (br s, 2H), 6.93 (d, 3,4-dihydro-2H-1-benzopyran-3- J = 8.4 Hz, 1H), 6.43 (d, J = 8.4 Hz, 1H), yl]thieno[2,3-b]pyridine-2- 6.27 (s, 1H), 4.33-4.29 (m, 1H), 4.17- carboxamide 4.13 (m, 1H), 4.02-3.98 (m, 2H), 3.90- 3.80 (m, 3H), 3.62-3.59 (m, 2H), 3.02- 2.98 (m, 4H), 2.87-2.85 (m, 2H), 2.59 (s, 3H). 210 3-amino-N-[(6S)-2-[(3S,4S)-4- 467 (DMSO-d6, 400 MHz) δ (ppm): 8.31 (d, +++ + amino-3-methoxy-3- J = 8.4 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), methylpyrrolidin-1-yl]-5,6,7,8- 7.32 (d, J = 8.4 Hz, 1H), 7.19-7.16 (m, tetrahydroquinolin-6-yl]-6- 3H), 6.20 (d, J = 8.4 Hz, 1H), 4.12-4.05 methylthieno[2,3-b]pyridine-2- (m, 1H), 3.59-3.55 (m, 1H), 3.47-3.44 carboxamide (m, 1H), 3.29-3.25 (m, 2H), 3.20-3.17 (s, 3H), 3.06-3.02 (m, 1H), 2.81-2.71 (m, 4H), 2.61-2.58 (s, 3H), 2.05-1.95 (m, 1H), 1.89-1.82 (m, 1H), 1.68-1.62 (m, 2H), 1.25 (s, 3H). 211 3-amino-N-[(6S)-2-[(3R,4R)-4- 467 (DMSO-d6, 400 MHz) δ (ppm): 8.31 (d, +++ + amino-3-methoxy-3- J = 8.0 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), methylpyrrolidin-1-yl]-5,6,7,8- 7.32 (d, J = 8.4 Hz, 1H), 7.18-7.16 (m, tetrahydroquinolin-6-yl]-6- 3H), 6.20 (d, J = 8.4 Hz, 1H), 4.12-4.05 methylthieno[2,3-b]pyridine-2- (m, 1H), 3.58-3.54 (m, 1H), 3.49-3.46 carboxamide (m, 1H), 3.28-3.25 (m, 2H), 3.20-3.16 (s, 3H), 3.07-3.02 (m, 1H), 2.81-2.67 (m, 4H), 2.59-2.55 (s, 3H), 2.05-1.95 (m, 1H), 1.89-1.86 (m, 1H), 1.65-1.55 (m, 2H), 1.25 (m, 3H). 212 3-amino-N-[(3R)-7-[(3S,4S)-3- 468 (DMSO-d6 400 MHz) δ (ppm): 8.32 (d, ++++ ++ methoxy-4- J = 8.4 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), (methylamino)pyrrolidin-1-yl]- 7.31 (d, J = 8.4 Hz, 1H), 7.21 (br s, 1H), 3,4-dihydro-2H-1-benzopyran-3- 6.86 (d, J = 8.4 Hz, 1H), 6.12-6.10 (m, yl]-6-methylthieno[2,3- 1H), 5.93 (s, 1H), 4.30-4.26 (m, 1H), b]pyridine-2-carboxamide 4.15-4.12 (m, 1H), 3.81-3.76 (m, 2H), 3.40-3.33 (m, 2H), 3.29 (s, 3H), 3.16- 3.11 (m, 2H), 2.99-2.96(m, 1H), 2.89- 2.81 (m, 2H), 2.58 (s, 3H), 2.31 (s, 3H), 1.86 (br s, 1H). 213 3-amino-N-[(3R)-7-[(3S,4S)-3- 496 (DMSO-d6, 400 MHz) δ (ppm): 8.32 (d, +++ ++ acetamido-4-methoxypyrrolidin- J = 8.4 Hz, 1H), 8.16 (d, J = 7.2 Hz, 1H), 1-yl]-3,4-dihydro-2H-1- 7.49 (d, J = 7.6 Hz, 1H), 7.31 (d, J = 8.0 benzopyran-3-yl]-6- Hz, 1H), 7.21 (br s, 1H), 6.89 (d, J = 8.0 methylthieno[2,3-b]pyridine-2- Hz, 1H), 6.16-6.13 (m, 1H), 5.96 (s, 1H), carboxamide 4.27 (br s, 2H), 4.16-4.13 (m, 1H), 3.92- 3.77 (m, 2H), 3.50-3.41 (m, 2H), 3.31 (s, 3H), 3.16-3.14 (m, 1H), 3.05-3.02 (m, 1H), 2.90-2.82 (m, 2H), 2.58 (s, 3H), 1.82 (s, 3H). 214 3-amino-N-[(3R)-7-[(4R)-4- 452 (DMSO-d6 400 MHz) δ (ppm): 8.32 (d, ++++ +++ amino-3,3-dimethylpyrrolidin-1- J = 8.4 Hz, 1H), 7.48 (br s, 1H), 7.31 (d, yl]-3,4-dihydro-2H-1- J = 8.4 Hz, 1H), 7.21 (br s, 2H), 6.85 (d, benzopyran-3-yl]-6- J = 8.4 Hz, 1H), 6.04 (d, J = 8.0 Hz, 1H), methylthieno[2,3-b]pyridine-2- 5.83 (s, 1H), 4.28-4.26 (m, 1H), 4.15- carboxamide 1.13 (m, 1H), 3.80-3.75 (m, 1H), 3.39- 3.32 (m, 1H), 3.09-3.01 (m, 2H), 2.94- 2.91 (m, 1H), 2.89-2.78 (m, 3H), 2.54 (s, 3H), 1.55 (br s, 2H), 1.05 (s, 3H), 0.90 (s, 3H). 215 3-amino-N-[(3R)-7-[(4S)-4- 452 (DMSO-d6, 400 MHz) δ (ppm): 8.32 (d, ++++ +++ amino-3,3-dimethylpyrrolidin-1- J = 8.0 Hz, 1H), 7.47 (br s, 1H), 7.31 (d, yl]-3,4-dihydro-2H-1- J = 8.0 Hz, 1H), 7.21 (br s, 2H), 6.84 (d, benzopyran-3-yl]-6- J = 8.4 Hz, 1H), 6.04 (d, J = 8.8 Hz, 1H), methylthieno[2,3-b]pyridine-2- 5.85 (s, 1H), 4.28-4.26 (m, 1H), 4.14- carboxamide 4.12 (m, 1H), 3.80-3.75 (m, 1H), 3.39- 3.32 (m, 1H), 3.09-3.01 (m, 2H), 2.94- 2.91 (m, 1H), 2.88-2.76 (m, 3H), 2.58 (s, 3H), 1.55 (br s, 2H), 1.05 (s, 3H), 0.90 (s, 3H). 216 N-[(6S)-2-[(3aS,6aS)- 449 (DMSO-d6, 400 MHz) δ (ppm): 8.31 (d, ++++ ++ octahydropyrrolo[2,3-c]pyrrol-1- J = 8.4 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), yl}-5,6,7,8-tetrahydroquinolin-6- 7.31 (d, J = 8.4 Hz, 1H), 7.23-7.16 (m, yl]-3-amino-6-methylthieno[2,3- 3H), 6.27 (d, J = 8.4 Hz, 1H), 4.16-4.12 b]pyridine-2-carboxamide (m, 2H), 3.49-3.45 (m, 2H), 3.40-3.33 (m, 1H), 2.90-2.63 (m, 9H), 2.58 (s, 3H), 2.05-1.98 (m, 2H), 1.90-1.69 (m, 2H). 217 N-[(6S)-2-[(3aR,6aR)- 449 (DMSO-d6, 400 MHz) δ (ppm): 8.31 (d, ++++ +++ octahydropyrrolo[2,3-c]pyrrol-1- J = 8.4 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), yl]-5,6,7,8-tetrahydroquinolin-6- 7.31 (d, J = 8.0 Hz, 1H), 7.20-7.16 (m, yl]-3-amino-6-methylthieno[2,3- 3H), 6.27 (d, J = 8.8 Hz, 1H), 4.16-4.12 b]pyridine-2-carboxamide (m, 2H), 3.50-3.36 (m, 3H), 2.90-2.63 (m, 9H), 2.59 (s, 3H), 2.05-1.99 (m, 2H), 1.88-1.71 (m, 2H). 218 N-[(6S)-2-[(3aS 6aS)- 463 (DMSO-d6, 400 MHz) δ (ppm): 7.60 (d, +++ ++ octahydropyrrolo[2,3-c]pyrrol-1- J = 8.0 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), yl]-5,6,7,8-tetrahydroquinolin-6- 7.04 (s, 1H), 6.82 (br s, 2H), 6.27 (d, J = yl]-3-amino-4,6- 8.4 Hz, 1H), 4.14-4.13 (m, 2H), 3.51- dimethylthieno[2,3-b]pyridine-2- 3.32 (m, 3H), 2.90-2.63 (m, 12H), 2.51 carboxamide (s, 3H), 2.03-1.98 (m, 2H), 1.87-1.69 (m, 2H). 219 N-[(6S)-2-[(3aR,6aR)- 463 (DMSO-d6, 400 MHz) δ (ppm): 7.61 (d, ++++ +++ octahydropyrrolo[2,3-c]pyrrol-1- J = 7.6 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), yl]-5,6,7,8-tetrahydroquinolin-6- 7.04 (s, 1H), 6.82 (br s, 2H), 6.26 (d, J = yl]-3-amino-4,6- 8.4 Hz, 1H), 4.14-4.12 (m, 2H), 3.50- dimethylthieno[2,3-b]pyridine-2- 3.41 (m, 1H), 3.39-3.33 (m, 2H), 2.91- carboxamide 2.62 (m, 12H), 2.51 (s, 3H), 2.05-1.99 (m, 2H), 1.90-1.69 (m, 2H). 220 N-[(3R)-7-[(3aS,6aS)- 468 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, ++++ +++ octahydropyrrolo[2,3-c]pyrrol-1- J = 8.4 Hz, 1H), 7.57 (br s, 1H), 7.32 (d, yl]-5-fluoro-3,4-dihydro-2H-1- J = 8.4 Hz, 1H), 7.23 (br s, 2H), 5.99 (d, benzopyran-3-yl]-3-amino-6- J = 11.2 Hz, 1H), 5.81 (s, 1H), 4.31-4.24 methylthieno[2,3-b]pyridine-2- (m, 1H), 4.18-4.15 (m, 1H), 3.89-3.81 carboxamide (m, 2H), 3.43-3.41 (m, 1H), 3.11-3.05 (m, 1H), 2.88-2.63 (m, 7H), 2.59 (s, 3H), 2.05-2.01 (m, 1H), 1.76-1.71 (m, 1H). 221 N-[(3R)-7-[(3aR,6aR)- 468 (DMSO-d6 400 MHz) δ (ppm): 8.34 (d, ++++ ++ octahydropyrrolo[2,3-c]pyrrol-1- J = 8.4 Hz, 1H), 7.58 (br s, 1H), 7.32 (d, yl]-5-fluoro-3,4-dihydro-2H-1- J = 8.0 Hz, 1H), 7.23 (br s, 2H), 6.01- benzopyran-3-yl]-3-amino-6- 5.98 (m, 1H), 5.82 (s, 1H), 4.31-4.24 (m, methylthieno[2,3-b]pyridine-2- 1H), 4.18-4.16 (m, 1H), 3.91-3.82 (m, carboxamide 2H), 3.39-3.35 (m, 1H), 3.11-3.05 (m, 1H), 2.88-2.64 (m, 7H), 2.60 (s, 3H), 2.06-2.00 (m, 1H), 1.77-1.70 (m, 1H). 222 N-[(3R)-7-[(3aS,6aS)- 482 (DMSO-d6, 400 MHz) δ (ppm): 7.60 (br ++++ +++ octahydropyrrolo[2,3-c]pyrrol-1- s, 1H), 7.05(s, 1H), 6.87 (br s, 2H), 5.99 yl]-5-fluoro-3,4-dihydro-2H-1- (d, J = 12.4 Hz, 1H), 5.81 (s, 1H), 4.30- benzopyran-3-yl]-3-amino-4,6- 4.26 (m, 1H), 4.17-4.15 (m, 1H), 3.91- dimethylthieno[2,3-b]pyridine-2- 3.81 (m, 2H), 3.38-3.34 (m, 1H), 3.11- carboxamide 3.05 (m, 1H), 2.88-2.63 (m, 10H), 2.57 (s, 3H), 2.08-1.99 (m, 1H), 1.78-1.70 (m, 1H). 223 N-[(3R)-7-[(3aR,6aR)- 482 (DMSO-d6 400 MHz) δ (ppm): 7.61 (br ++++ +++ octahydropyrrolo[2,3-c]pyrrol-1- s, 1H), 7.05(s, 1H), 6.87 (br s, 2H), 5.99 yl]-5-fluoro-3,4-dihydro-2H-1- (d, J = 12.8 Hz, 1H), 5.81 (s, 1H), 4.29- benzopyran-3-yl]-3-amino-4,6- 4.25 (m, 1H), 4.17-4.15 (m, 1H), 3.90- dimethylthieno[2,3-b]pyridine-2- 3.81 (m, 2H), 3.39-3.35 (m, 1H), 3.11- carboxamide 3.05 (m, 1H), 2.88-2.64 (m, 10H), 2.55 (s, 3H), 2.06-2.01 (m, 1H), 1.78-1.70 (m, 1H). 224 N-[(3R)-7-[(3aR,7aS)- 464 (DMSO-d6, 400 MHz) δ (ppm): 8.32 (d, ++++ +++ octahydro-1H-pyrrolo[2,3- J = 8.0 Hz, 1H), 7.48 (br s, 1H), 7.31 (d, c]pyridin-1-yl]-3,4-dihydro-2H-1- J = 8.4 Hz, 1H), 7.21 (br s, 2H), 6.84 (d, benzopyran-3-yl]-3-amino-6- J = 8.4 Hz, 1H), 6.14 (d, J = 8.0 Hz, 1H), methylthieno[2,3-b]pyridine-2- 5.91 (s, 1H), 4.28-4.26 (m, 1H), 4.14- carboxamide 4.12 (m, 1H), 3.80-3.75 (m, 1H), 3.60- 3.55 (m, 1H), 3.28-3.23 (m, 1H), 3.14- 3.06 (m, 2H), 2.83-2.80 (m, 2H), 2.71- 2.66 (m, 1H), 2.58-2.54 (m, 4H), 2.34- 2.28 (m, 1H), 2.25-2.19 (m, 1H), 2.17- 2.07 (m, 1H), 1.85-1.75 (m, 2H), 1.61- 158 (m, 1H). 225 N-[(3R)-7-1(3aS,7aR)- 464 (DMSO-d6 400 MHz) δ (ppm): 8.32 (d, ++++ ++++ octahydro-1H-pyrrolo[2,3- J = 8.0 Hz, 1H), 7.49 (br s, 1H), 7.31 (d, c]pyridin-1-yl]-3,4-dihydro-2H-1- J = 8.0 Hz, 1H), 7.21 (br s, 2H), 6.84 (d, benzopyran-3-yl]-3-amino-6- J = 8.0 Hz, 1H), 6.13 (d, J = 7.6 Hz, 1H), methylthieno[2,3-b]pyridine-2- 5.91 (s, 1H), 4.28-4.25 (m, 1H), 4.14- carboxamide 4.12 (m, 1H), 3.80-3.75 (m, 1H), 3.60- 3.57 (m, 1H), 3.28-3.23 (m, 1H), 3.14- 3.08 (m, 2H), 2.87-2.77 (m, 2H), 2.69- 2.67 (m, 1H), 2.58-2.54 (m, 4H), 2.32- 2.28 (m, 1H), 2.25-2.07 (m, 2H), 1.87- 1.76 (m, 2H), 1.61-1.58 (m, 1H). 226 N-[(3R)-7-[(3aS,6aS)- 464 (DMSO-d6 400 MHz) δ (ppm): 7.54 (br ++++ +++ octahydropyrrolo[2,3-c]pyrrol-1- s, 1H), 705(s, 1H), 6.89-6.86 (m, 3H), yl]-3,4-dihydro-2H-1- 6.15 (d, J = 8.8 Hz, 1H), 5.96 (s, 1H), benzopyran-3-yl]-3-amino-4,6- 4.31-4.28 (m, 1H), 4.16-4.12 (m, 1H), dimethylthieno[2,3-b]pyridine-2- 3.89-3.82 (m, 1H), 3.80-3.77 (m, 1H), carboxamide 3.40-3.32 (m, 1H), 3.08-3.02 (m, 1H), 2.90-2.77 (m, 8H), 2.67-2.59 (m, 2H), 2.51 (m, 3H), 2.06-2.00 (m, 1H), 1.78- 1.69 (m, 1H). 227 N-[(3R)-7-[(3aR,6aR)- 464 (DMSO-d6, 400 MHz) δ (ppm): 7.55 (br ++++ +++ octahydropyrrolo[2,3-c]pyrrol-1- s, 1H), 7.04 (s, 1H), 6.89-6.86 (m, 3H), yl]-3,4-dihydro-2H-1- 6.18-6.15 (m, 1H), 5.99-5.98 (m, 1H), benzopyran-3-yl]-3-amino-4,6- 4.31-4.27 (m, 1H), 4.16-4.13 (m, 1H), dimethylthieno[2,3-b]pyridine-2- 4.02-3.97 (m, 1H), 3.83-3.80 (m, 1H), carboxamide 3.46-3.41 (m, 1H), 3.12-3.01 (m, 2H), 2.99-2.81 (m, 6H), 2.73-2.70 (m, 3H), 2.51 (m, 3H), 2.09-2.02 (m, 1H), 1.86- 1.79 (m, 1H). 228 (6aS,7aR)-N-[(3R)-8-cyano-7- 475 (DMSO-d6, 400 MHz) δ (ppm): 8.29 (d, ++ ++ {3,8-diazabicyclo[3.2.1]octan-3- J = 2.0 Hz, 1H), 8.19 (d, J = 6.4 Hz, 1H), yl}-5-fluoro-3,4-dihydro-2H-1- 7.86 (d, J = 2.0 Hz, 1H), 6.63 (br s, 1H), benzopyran-3-yl]- 6.49 (d, J = 11.6 Hz, 1H), 4.35-4.31 (m, 5H,6H,6aH,7H,7aH- 2H), 4.15-4.10 (m, 1H), 3.45-3.42 (m, cyclopropa[c]1,8-naphthyridine- 2H), 3.39-3.27 (m, 4H), 2.98-2.88 (m, 2-carboxamide 3H), 2.75-2.69 (m, 1H), 1.99-1.85 (m, 3H), 1.77-1.64 (m, 2H), 0.96-0.90 (m, 2H). 229 (6aR,7aS)-N-[(3R)-8-cyano-7- 475 (DMSO-d6, 400 MHz) δ (ppm): 8.28 (d, ++ + {3,8-diazabicyclo[3.2.1]octan-3- J = 20 Hz, 1H), 8.19 (d, J = 64 Hz, 1H), yl}-5-fluoro-3,4-dihydro-2H-1- 7.85 (d, J = 2.0 Hz, 1H), 6.63 (br s, 1H), benzopyran-3-yl]- 6.49 (d, J = 12.0 Hz, 1H), 4.35-4.30 (m, 5H,6H,6aH,7H,7aH- 2H), 4.15-4.10 (m, 1H), 3.44-3.42 (m, cyclopropa[c]1,8-naphthyridine- 2H), 3.38-3.26 (m, 4H), 2.97-2.88 (m, 2-carboxamide 3H), 2.74-2.68 (m, 1H), 1.98-1.87 (m, 3H), 1.76-1.64 (m, 2H), 0.96-0.90 (m, 2H). 230 3-amino-N-[(3R)-8-cyano-7- 507 (DMSO-d6, 400 MHz) δ (ppm): 7.73 (d, ++++ ++ {3,8-diazabicyclo[3.2.1]octan-3- J = 6.8 Hz, 1H), 7.04 (s, 1H), 6.88 (br s, yl}-5-fluoro-3,4-dihydro-2H-1- 2H), 6.48 (d, J = 11.6 Hz, 1H), 4.39-4.32 benzopyran-3-yl]-4,6- (m, 2H), 4.11-4.06 (m, 1H), 3.46-3.44 dimethylthieno[2,3-b]pyridine-2- (m, 2H), 3.31-3.27 (m, 5H), 2.94-2.88 carboxamide (m, 3H), 2.80-2.76 (m, 1H), 2.72 (s, 3H), 1.92-1.85 (m, 2H), 1.68-1.65 (m, 2H). 231 N-[(3R)-7-[(3aR,6R,7aR)-6- 478 (DMSO-d6 400 MHz) δ (ppm): 8.33 (d, ++++ ++++ amino-octahydro-1H-indol-1-yl]- J = 8.0 Hz, 1H), 7.50 (d, J = 7.2 Hz, 1H), 3,4-dihydro-2H-1-benzopyran-3- 7.32 (d, J = 8.4 Hz, 1H), 7.22 (br s, 2H), yl]-3-amino-6-methylthieno[2,3- 6.84 (d, J = 8.0 Hz, 1H), 6.15 (d, J = 8.4 b]pyridine-2-carboxamide Hz, 1H), 5.96 (s 1H), 4.31-4.22 (m, 1H), 4.15-4.12 (m, 1H), 3.89-3.87 (m, 1H), 3.81-3.76 (m, 1H), 3.32-3.25 (m, 1H), 3.13-3.11 (m, 1H), 2.95-2.89 (m, 1H), 2.85-2.77 (m, 2H), 2.59 (s, 3H), 2.22- 2.19 (m, 1H), 2.03-1.95 (m, 1H), 1.90- 1.55 (m, 6H), 1.50-1.36 (m, 2H), 1.26- 1.18(m, 1H). 232 N-[(3R)-7-[(3aR,6S,7aR)-6- 478 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, ++++ +++ amino-octahydro-1H-indol-1-yl]- J = 8.4 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 3,4-dihydro-2H-1-benzopyran-3- 7.32 (d, J = 8.0 Hz, 1H), 7.21 (br s, 2H), yl]-3-amino-6-methylthieno[2,3- 6.84 (d, J = 8.0 Hz, 1H), 6.13 (d, J = 7.6 b]pyridine-2-carboxamide Hz, 1H), 5.93 (s, 1H), 4.31-4.23 (m, 1H), 4.15-4.12 (m, 1H), 3.91-3.68 (m, 2H), 3.22-3.17 (m, 2H), 2.84-2.82 (m, 2H), 2.68-2.59 (m, 4H), 2.30-2.17 (m, 1H), 2.09-1.94 (m, 2H), 1.86-1.67 (m, 3H), 1.60-1.53 (m, 1H), 1.21-1.16 (m, 1H), 0.84-0.74 (m, 1H). 233 N-[(3R)-7-[(3aS,6R,7aS)-6- 478 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, ++++ ++++ amino-octahydro-1H-indol-1-yl]- J = 8.0 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 3,4-dihydro-2H-1-benzopyran-3- 7.32 (d, J = 8.4 Hz, 1H), 7.21 (br s, 2H), yl]-3-amino-6-methylthieno[2,3- 6.84 (d, J = 8.4 Hz, 1H), 6.13 (d, J = 8.0 b]pyridine-2-carboxamide Hz, 1H), 5.93 (s, 1H), 4.31-4.23 (m, 1H), 4.15-4.12 (m, 1H), 3.91-3.68 (m, 2H), 3.22-3.17 (m, 2H), 2.84-2.82 (m, 2H), 2.68-2.59 (m, 4H), 2.30-2.17 (m, 1H), 2.12-2.08 (m, 1H), 2.04-1.96 (m, 1H), 1.89-1.67 (m, 4H), 1.60-1.56 (m, 1H), 1.24-1.19 (m, 1H), 0.87-0.77 (m, 1H). 234 N-[(3R)-7-[(3aS,6S,7aS)-6- 478 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, ++++ +++ amino-octahydro-1H-indol-1-yl]- J = 8.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 3,4-dihydro-2H-1-benzopyran-3- 7.32 (d, J = 7.6 Hz, 1H), 7.21 (br s, 2H), yl]-3-amino-6-methylthieno[2,3- 6.84 (d, J = 7.6 Hz, 1H), 6.16 (d, J = 8.4 b]pyridine-2-carboxamide Hz, 1H), 5.96 (s, 1H), 4.31-4.22 (m, 1H), 4.16-4.12 (m, 1H), 3.89-3.87 (m, 1H), 3.81-3.76 (m, 1H), 3.32-3.25 (m, 1H), 3.13-3.11 (m, 1H), 2.93-2.88 (m, 1H), 2.84-2.78 (m, 2H), 2.59 (s, 3H), 2.22- 2.19 (m, 1H), 2.03-1.96 (m, 1H), 1.90- 1.55 (m, 5H), 1.51-1.37 (m, 2H), 1.24- 1.18(m, 1H). 235 N-[(3R)-7-[(3aS,7aR)- 464 (DMSO-d6, 400 MHz) δ (ppm): 8.32 (d, ++++ +++ octahydro-1H-pyrrolo[3,2- J = 8.0 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), c]pyridin-1-yl]-3,4-dihydro-2H-1- 7.31(d, J = 8.0 Hz, 1H), 7.22 (s, 2H), benzopyran-3-yl]-3-amino-6- 6.83(d, J = 8.0 Hz, 1H), 6.13 (d, J = 8.0 methylthieno[2,3-b]pyridine-2- Hz, 1H), 5.92 (s, 1H), 4.27 (br s, 1H), carboxamide 4.14-4.12 (m, 1H), 3.80-3.75 (m, 1H), 3.72-3.68 (m, 1H), 3.25-3.16 (m, 2H), 2.94-2.75 (m, 5H), 2.59 (s, 3H), 2.43- 2.33 (m, 1H), 2.25-2.16 (m, 2H), 1.90- 1.82 (m, 2H), 1.19-1.10 (m, 1H). 236 N-[(3R)-7-[(3aR,7aS)- 464 (DMSO-d6, 400 MHz) δ (ppm): 8.32 (d, ++++ +++ octahydro-1H-pyrrolo[3,2- J = 8.0 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), c]pyridin-1-yl]-3,4-dihydro-2H-1- 7.32 (d, J = 8.8 Hz, 1H), 7.21 (s, 2H), benzopyran-3-yl]-3-amino-6- 6.83 (d, J = 8.4 Hz, 1H), 6.14 (d, J = 8.4 methylthieno[2,3-b]pyridine-2- Hz, 1H), 5.92 (s, 1H), 4.27 (br s, 1H), carboxamide 4.14-4.12 (m, 1H), 3.80-3.75 (m, 1H), 3.70-3.68 (m, 1H), 3.25-3.16 (m, 2H), 2.93-2.80 (m, 5H), 2.59 (s, 3H), 2.41- 2.15 (m, 3H), 1.93-1.81 (m, 2H), 1.18- 1.09 (m, 1H). 237 N-[(3R)-7-[(4aR,7aR)-4,4- 500 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, ++++ ++ difluoro-octahydro-1H- J = 8.0 Hz, 1H), 7.49 (br s, 1H), 7.32 (d, pyrrolo[3,4-b]pyridin-6-yl]-3,4- J = 8.4 Hz, 1H), 7.22 (br s, 2H), 6.88 (d, dihydro-2H-1-benzopyran-3-yl]- J = 8.0 Hz, 1H), 6.10 (d, J = 8.4, 1H), 3-amino-6-methylthieno[2,3- 5.91 (s, 1H), 4.27-4.25 (m, 1H), 4.16- b]pyridine-2-carboxamide 4.13 (m, 1H), 3.82-3.77 (m, 1H), 3.45- 3.40 (m, 2H), 3.39-3.33 (m, 1H) 3.11- 3.08 (m, 1H), 2.97-2.90 (m, 1H), 2.86- 2.82 (m, 2H), 2.79-2.74 (m, 1H), 2.68- 2.64 (m, 1H), 2.59 (s, 3H), 2.40-2.25 (m, 1H), 2.06-1.81 (m, 3H). 238 N-[(3R)-7-[(4aS,7aS)-4,4- 500 (DMSO-d6 400 MHz) δ (ppm): 8.33 (d, ++++ ++ difluoro-octahydro-1H- J = 8.0 Hz, 1H), 7.49 (br s, 1H), 7.32 (d, pyrrolo[3,4-b]pyridin-6-yl]-3,4- J = 8.4 Hz, 1H), 7.22 (br s, 2H), 6.88 (d, dihydro-2H-1-benzopyran-3-yl]- J = 8.0 Hz, 1H), 6.10 (d, J = 6.8 Hz, 1H), 3-amino-6-methylthieno[2,3- 5.91 (s, 1H), 4.28-4.26 (m, 1H), 4.16- b]pyridine-2-carboxamide 4.14 (m, 1H), 3.81-3.76 (m, 1H), 3.45- 3.40 (m, 2H), 3.39-3.28 (m, 1H), 3.11- 3.08 (m, 1H), 2.97-2.90 (m, 1H), 2.86- 2.80 (m, 2H), 2.78-2.72 (m, 1H), 2.67- 2.64 (m, 1H), 2.59 (s, 3H), 2.43-2.33 (m, 1H), 2.08-1.87 (m, 3H). 239 3-amino-N-[(6S)-2-[(3S,4S)-3- 467 (DMSO-d6, 400 MHz) δ (ppm): 8.31 (d, ++ + amino-4-methoxy-3- J = 8.0 Hz, 1H), 7.56 (br s, 1H), 7.31 (d, methylpyrrolidin-1-yl]-5,6,7,8- J = 8.4 Hz, 1H), 7.19-7.16 (m, 3H), 6.20 tetrahydroquinolin-6-yl]-6- (d, J = 8.4 Hz, 1H), 4.15-4.12 (m, 1H), methylthieno[2,3-b]pyridine-2- 3.69-3.65 (m, 1H), 3.48-3.46 (m, 1H), carboxamide 3.35-3.32 (m, 1H), 3.28-3.25 (m, 3H), 3.19-3.17 (m, 2H), 2.81-2.67 (m, 4H), 2.59 (s, 3H), 2.01-1.98 (m, 1H), 1.89- 1.79 (m, 1H), 1.68 (br s, 2H), 1.17 (s, 3H). 240 3-amino-N-[(6S)-2-[(3R,4R)-3- 467 (DMSO-d6 400 MHz) δ (ppm): 8.31 (d, ++ + amino-4-methoxy-3- J = 8.0 Hz, 1H), 7.57(br s, 1H), 7.31 (d, methylpyrrolidin-1-yl]-5,6,7,8- J = 8.4 Hz, 1H), 7.19-7.16 (m, 3H), 6.20 tetrahydroquinolin-6-yl]-6- (d, J = 8.4 Hz, 1H), 4.16-4.12 (m, 1H), methylthieno[2,3-b]pyridine-2- 3.68-3.64 (m, 1H), 3.48-3.46 (m, 1H), carboxamide 3.38-3.31 (m, 1H), 3.28-3.25 (m, 3H), 3.20-3.16 (m, 2H), 2.81-2.67 (m, 4H), 2.59 (s, 3H), 2.01-1.98 (m, 1H), 1.95- 1.88 (m, 1H), 1.73 (br s, 2H), 1.17 (s, 3H). 241 3-amino-N-[(3R)-6-cyano-7- 507 (DMSO-d6, 400 MHz) δ (ppm): 7.70 (d, ++++ ++++ {3,8-diazabicyclo[3.2.1]octan-3- J = 6.8 Hz, 1H), 7.05 (s, 1H), 6.89 (br s, yl}-5-fluoro-3,4-dihydro-2H-1- 2H), 6.29 (s, 1H), 4.34-4.25 (m, 2H), benzopyran-3-yl]-4,6- 4.06-4.01 (m, 1H), 3.48-3.46 (m, 2H), dimethylthieno[2,3-b]pyridine-2- 3.35-3.28 (m, 5H), 2.96-2.88 (m, 3H), carboxamide 2.82-2.76 (m, 1H), 2.73 (s, 3H), 1.90- 1.85 (m, 2H), 1.68-1.67 (m, 2H). 242 N-[(3R)-7-[(4aR,7aR)- 464 (DMSO-d6, 400 MHz) δ (ppm): 8.31 (d, ++++ +++ octahydro-1H-pyrrolo[3,4- J = 8.0 Hz, 1H), 7.54 (br s, 1H), 7.31 (d, b]pyridin-1-yl]-3 ,4-dihydro-2H-1- J = 8.0 Hz, 1H), 7.22 (br s, 2H), 6.94- benzopyran-3-yl]-3-amino-6- 6.89 (m, 1H), 6.53-6.51 (m, 1H), 6.36- methylthieno[2,3-b]pyridine-2- 6.30 (m, 1H), 4.32-4.28 (m, 1H), 4.16- carboxamide 4.11 (m, 2H), 3.82-3.77 (m, 1H), 3.28- 3.10 (m, 2H), 3.00-2.95(m, 1H), 2.88- 2.75 (m, 4H), 2.64-2.55 (m, 4H), 2.27- 2.07 (m, 1H), 1.78-1.60 (m, 2H), 1.48- 1.40 (m, 2H). 243 N-[(3R)-7-[(4aS,7aS)- 464 (DMSO-d6, 400 MHz) δ (ppm): 8.31 (d, ++++ ++++ octahydro-1H-pyrrolo[3,4- J = 8.0 Hz, 1H), 7.56 (br s, 1H), 7.31 (d, b]pyridin-1-yl]-3,4-dihydro-2H-1- J = 8.8 Hz, 1H), 7.22 (br s, 2H), 6.94- benzopyran-3-yl]-3-amino-6- 6.88 (m, 1H), 6.59-6.51 (m, 1H), 6.37- methylthieno[2,3-b]pyridine-2- 6.30 (m, 1H), 4.36-4.14 (m, 3H), 3.82- carboxamide 3.78 (m, 1H), 3.32-2.95 (m, 3H), 2.88- 2.68 (m, 4H), 2.63-2.51 (m, 4H), 2.30- 2.03 (m, 1H), 1.77-1.60 (m, 2H),1.50- 1.30 (m, 2H). 244 3-amino-N-[(3R)-7-[(2R,5R)-5- 506 (MeOH-d4, 400 MHz) δ (ppm): 8.22 (d, ++++ ++++ amino-2- J = 8.0 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), (trifluoromethyl)piperidin-1-yl]- 6.96 (d, J = 8.4 Hz, 1H), 6.57 (d, J = 8.4 3,4-dihydro-2H-1-benzopyran-3- Hz, 1H), 6.45 (s, 1H), 4.47-4.38 (m, yl]-6-methylthieno[2,3- 2H), 4.27-4.25 (m, 1H), 3.96-3.91 (m, b]pyridine-2-carboxamide 1H), 3.62-3.60 (m, 1H), 3.03-2.84 (m, 4H), 2.65 (s, 3H), 2.15-2.12 (m, 1H), 2.02-1.89 (m, 2H), 1.60-1.50 (m, 1H). 245 3-amino-N-[(3R)-7-[(2S,5S)-5- 506 (MeOH-d4, 400 MHz) δ (ppm): 8.22 (d, ++++ +++ amino-2- J = 8.4 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), (trifluoromethyl)piperidin-1-yl]- 6.97 (d, J = 8.4 Hz, 1H), 6.57 (d, J = 8.8 3,4-dihydro-2H-1-benzopyran-3- Hz, 1H), 6.45 (s, 1H), 4.96-4.40 (m, yl]-6-methylthieno[2,3- 2H), 4.27-4.24 (m, 1H), 3.97-3.92 (m, b]pyridine-2-carboxamide 1H), 3.63-3.60 (m, 1H), 3.03-2.81 (m, 4H), 2.65 (s, 3H), 2.15-2.12 (m, 1H), 2.02-1.88 (m, 2H), 1.57-1.50 (m, 1H). 246 3-amino-N-[(3R)-7-[(2R,5S)-5- 506 (MeOH-d4, 400 MHz) δ (ppm): 8.22 (d, ++++ ++++ amino-2- J = 8.4 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), (trifluoromethyl)piperidin-1-yl]- 6.98 (d, J = 8.4 Hz, 1H), 6.64 (d, J = 8.4 3,4-dihydro-2H-1-benzopyran-3- Hz, 1H), 6.50 (s, 1H), 4.48-4.46 (m, 2H), yl]-6-methylthieno[2,3- 4.27-4.25 (m, 1H), 3.97-3.93 (m, 1H), b]pyridine-2-carboxamide 3.45-3.37 (m, 2H), 3.18 (m, 1H), 3.04- 2.99 (m, 1H), 2.91-2.85 (m, 1H), 2.68 (s, 3H), 2.33-2.26 (m, 1H), 2.06-1.99 (m, 1H), 1.92-1.89 (m, 1H), 1.67-1.62 (m, 1H). 247 3-amino-N-[(3R)-7-[(2S,5R)-5- 506 (MeOH-d4, 400 MHz) δ (ppm): 8.22 (d, ++++ +++ amino-2- J = 8.4 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), (trifluoromethyl)piperidin-1-yl]- 6.98 (d, J = 8.8 Hz, 1H), 6.64 (d, J = 7.2 3,4-dihydro-2H-1-benzopyran-3- Hz, 1H), 6.51 (s, 1H), 4.52-4.45 (m, 2H), yl]-6-methylthieno[2,3- 4.28-4.25 (m, 1H), 3.96-3.91 (m, 1H), b]pyridine-2-carboxamide 3.50-3.38 (m, 2H), 3.28-3.24 (m, 1H), 3.04-2.99 (m, 1H), 2.91-2.85 (m, 1H), 2.79 (s, 3H), 2.33-2.26 (m, 1H), 2.12- 2.01 (m, 1H), 1.98-1.91 (m, 1H), 1.74- 1.66 (m, 1H). 248 N-[(3R)-7-[(3aS)-3a-amino- 464 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, ++++ ++ octahydrocyclopenta[c]pyrrol-2- J = 8.4 Hz, 1H), 7.49 (br s, 1H), 7.32 (d, yl]-3,4-dihydro-2H-1- J = 8.0 Hz, 1H), 7.21 (br s, 2H), 6.89 (d, benzopyran-3-yl]-3-amino-6- J = 8.0 Hz, 1H), 6.20-6.18 (m, 1H), 6.00 methylthieno[2,3-b]pyridine-2- (d, J = 2.4 Hz, 1H), 4.30-4.27 (m, 1H), carboxamide 4.16-4.13 (m, 1H), 3.82-3.77 (m, 1H), 3.50-3.45 (m, 1H), 3.27-3.25 (m, 1H), 3.17-3.15 (m, 1H), 2.96-2.92 (m, 1H), 2.86-2.83 (m, 2H), 2.58 (s, 3H), 2.42- 2.41 (m, 1H), 2.02-1.98 (m, 1H), 1.82- 1.68 (m, 5H), 1.50-1.45 (m, 1H). 249 N-[(3R)-7-[(3aR)-3a-amino- 464 (DMSO-d6 400 MHz) δ (ppm): 8.33 (d, ++++ +++ octahydrocyclopenta[c]pyrrol-2- J = 8.4 Hz, 1H), 7.49 (br s, 1H), 7.32 (d, yl]-3,4-dihydro-2H-1- J = 8.4 Hz, 1H), 7.21 (br s, 2H), 6.89 (d, benzopyran-3-yl]-3-amino-6- J = 8.4 Hz, 1H), 6.22-6.19 (m, 1H), 6.01 methylthieno[2,3-b]pyridine-2- (d, J = 2.0 Hz, 1H), 4.30-4.27 (m, 1H), carboxamide 4.16-4.13 (m, 1H), 3.82-3.77 (m, 1H), 3.52-3.48 (m, 1H), 3.27-3.18 (m, 2H), 2.95-2.92 (m, 1H), 2.86-2.83 (m, 2H), 2.58 (s, 3H), 2.50-2.44 (m, 1H), 1.99- 1.98 (m, 1H), 1.86-1.68 (m, 4H), 1.46- 1.45 (m, 1H). 250 3-amino-N-[(3R)-7-[(3R,4R)-3- 486 (DMSO-d6, 400 MHz) δ (ppm): 8.32 (d, ++++ ++ amino-4- J = 8.0 Hz, 1H), 7.56 (br s, 1H), 7.32 (d, (methoxymethyl)pyrrolidin-1-yl]- J = 8.4 Hz, 1H), 7.23 (br s, 2H), 5.94- 5-fluoro-3,4-dihydro-2H-1- 5.91 (m, 1H), 5.75 (s, 1H), 4.27-4.21 (m, benzopyran-3-yl]-6- 1H), 4.17-4.14 (m, 1H), 3.85-3.80 (m, methylthieno[2,3-b]pyridine-2- 1H), 3.59-3.55(m, 2H), 3.40-3.20 (m, carboxamide 6H), 3.09-3.05 (m, 1H), 2.97-2.94 (m, 1H), 2.83-2.81 (m, 1H), 2.75-2.68 (m, 1H), 2.59 (s, 3H), 2.43-2.41 (m, 1H), 1.90 (br s, 2H). 251 3-amino-N-[(3R)-7-[(3S,4S)-3- 486 (DMSO-d6 400 MHz) δ (ppm): 8.32 (d, ++++ +++ amino-4- J = 8.0 Hz, 1H), 7.55 (br s, 1H), 7.31 (d, (methoxymethyl)pyrrolidin-1-yl]- J = 8.0 Hz, 1H), 7.23 (br s, 2H), 5.95- 5-fluoro-3,4-dihydro-2H-1- 5.91 (m, 1H), 5.75 (s, 1H), 4.28-4.21 (m, benzopyran-3-yl]-6- 1H), 4.17-4.14 (m, 1H), 3.85-3.81 (m, methylthieno[2,3-b]pyridine-2- 1H), 3.59-3.55 (m, 2H), 3.41-3.21 (m, carboxamide 6H), 3.10-3.05 (m, 1H), 2.98-2.95 (m, 1H), 2.83-2.82 (m, 1H), 2.75-2.68 (m, 1H), 2.59 (s, 3H), 2.46-2.43 (m, 1H), 2.11 (br s, 2H). 252 3-amino-N-[(2S)-6-[(3R,4R)-3- 466 (DMSO-d6, 400 MHz) δ (ppm): 8.30 (d, +++ ++ amino-4- J = 8.4 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), (methoxymethyl)pyrrolidin-1-yl]- 7.30 (d, J = 8.4 Hz, 1H), 7.14 (br s, 2H), 1,2,3,4-tetrahydronaphthalen-2- 6.85 (d, J = 8.0 Hz, 1H), 6.29 (dd, J = yl]-6-methylthieno[2,3- 8.4, 2.4 Hz, 1H), 6.19 (s, 1H), 4.13-4.07 b]pyridine-2-carboxamide (m, 1H), 3.60-3.54 (m, 2H), 3.41-3.31 (m, 1H), 3.28 (s, 3H), 3.26-3.22 (m, 1H), 3.11-3.06 (m, 1H), 2.97-2.94 (m, 1H), 2.80-2.72 (m, 5H), 2.58 (s, 3H), 2.50- 2.41 (m, 1H), 1.98-1.94 (m, 1H), 1.79- 1.62 (m, 3H). 253 3-amino-N-[(2S)-6-[(3S,4S)-3- 466 (DMSO-d6, 400 MHz) δ (ppm): 8.30 (d, ++++ ++ amino-4- J = 8.4 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), (methoxymethyl)pyrrolidin-1-yl]- 7.31 (d, J = 7.6 Hz, 1H), 7.15 (br s, 2H), 1,2,3,4-tetrahydronaphthalen-2- 6.86 (d, J = 8.0 Hz, 1H), 6.29 (dd, J = yl]-6-methylthieno[2,3- 8.4, 2.4 Hz, 1H), 6.20 (s, 1H), 4.13-4.07 b]pyridine-2-carboxamide (m, 1H), 3.61-3.55 (m, 2H), 3.41-3.33 (m, 2H), 3.28 (s, 3H), 3.25-3.23 (m, 1H), 3.11-3.06 (m, 1H), 2.97-2.95 (m, 1H), 2.81-2.72 (m, 5H), 2.59 (s, 3H), 2.50- 2.41 (m, 1H), 1.98-1.94 (m, 1H), 1.79- 1.62 (m, 2H). 254 3-amino-N-[(6S)-2-[(3S,4R)-3- 467 (DMSO-d6 400 MHz) δ (ppm): 8.30 (d, +++ + amino-4-ethoxypyrrolidin-1-yl]- J = 8.4 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 5,6,7,8-tetrahydroquinolin-6-yl]- 7.30 (d, J = 8.0 Hz, 1H), 7.19-7.14 (m, 3 6-methylthieno[2,3-b]pyridine-2- H), 6.20 (d, J = 8.4 Hz, 1H), 4.12 (br s, carboxamide 1H), 3.84 (s, 1H), 3.60-3.42 (m, 6H), 3.03-2.98 (m, 1H), 2.78-2.67 (m, 4H), 2.58 (s, 3H), 2.01-1.97 (m, 1H), 1.89- 1.80 (m, 1H), 1.62 (br s, 2H), 1.17-1.12 (m, 3H). 255 3-amino-N-[(6S)-2-[(3R,4S)-3- 467 (DMSO-d6 400 MHz) δ (ppm): 8.30 (d, +++ + amino-4-ethoxypyrrolidin-1-yl]- J = 8.4 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 5,6,7,8-tetrahydroquinolin-6-yl]- 7.30 (d, J = 8.4 Hz, 1H), 7.19-7.14 (m, 3 6-methylthieno[2,3-b]pyridine-2- H), 6.20 (d, J = 8.4 Hz, 1H), 4.12 (br s, carboxamide 1H), 3.84 (s, 1H), 3.60-3.43 (m, 6H), 2.99-2.97 (m, 1H), 2.77-2.67 (m, 4H), 2.58 (s, 3H), 2.01-1.98 (m, 1H), 1.87- 1.82 (m, 1H), 1.62 (br s, 2H), 1.16-1.13 (m, 3H). 256 3-amino-N-[(3R)-7-[(4S)-4- 460 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, ++++ ++ amino-3,3-difluoropyrrolidin-1- J = 8.4 Hz, 1H), 7.50 (br s, 1H), 7.32 (d, yl]-3,4-dihydro-2H-1- J = 8.4 Hz, 1H), 7.22 (br s, 2H), 6.93 (d, benzopyran-3-yl]-6- J = 8.4 Hz, 1H), 6.16 (d, J = 6.4 Hz, 1H), methylthieno[2,3-b]pyridine-2- 5.99 (s, 1H), 4.29-4.27 (m, 1H), 4.17- carboxamide 4.14 (m, 1H), 3.83-3.81 (m, 1H), 3.69- 3.58 (m, 4H), 2.99-2.95 (m, 1H), 2.87- 2.85 (m, 2H), 2.59 (s, 3H), 1.93 (br s, 2H). 257 3-amino-N-[(3R)-7-[(4R)-4- 460 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, ++++ +++ amino-3,3-difluoropyrrolidin-1- J = 8.4 Hz, 1H), 7.50 (br s, 1H), 7.32 (d, yl]-3,4-dihydro-2H-1- J = 8.4 Hz, 1H), 7.22 (br s, 2H), 6.93 (d, benzopyran-3-yl]-6- J = 8.0 Hz, 1H), 6.16 (d, J = 8.0 Hz, 1H), methylthieno[2,3-b]pyridine-2- 5.99 (s, 1H), 4.29-4.27 (m, 1H), 4.18- carboxamide 4.15 (m, 1H), 3.84-3.81 (m, 1H), 3.69- 3.58 (m, 4H), 2.97-2.95 (m, 1H), 2.87- 2.85 (m, 2H), 2.59 (s, 3H), 1.94 (br s, 2H). 258 3-amino-N-[(3R)-7-[(8R)-8- 466 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, ++++ ++ amino-2-oxa-6- J = 8.4 Hz, 1H), 7.48 (br s, 1H), 7.32 (d, azaspiro[3.4]octan-6-yl]-3,4- J = 8.0 Hz, 1H), 7.21 (br s, 2H), 6.87 (d, dihydro-2H-1-benzopyran-3-yl]- J = 8.4 Hz, 1H), 6.01 (d, J = 8.0 Hz, 1H), 6-methylthieno[2,3-b]pyridine-2- 5.91 (s, 1H), 4.83-4.81 (m, 1H), 4.48- carboxamide 4.37 (m, 3H), 4.31-4.21 (m, 1H), 4.16- 4.13 (m, 1H), 3.82-3.77 (m, 1H), 3.56- 3.43 (m, 3H), 3.34-3.32 (m, 1H), 2.89- 2.79 (m, 3H), 2.59 (s, 3H), 2.18 (br s, 2H). 259 3-amino-N-[(3R)-7-[(8S)-8- 466 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, ++++ ++ amino-2-oxa-6- J = 8.4 Hz, 1H), 7.48 (br s, 1H), 7.32 (d, azaspiro[3.4]octan-6-yl]-3,4- J = 8.0 Hz, 1H), 7.21 (br s, 2H), 6.87 (d, dihydro-2H-1-benzopyran-3-yl]- J = 8.8 Hz, 1H), 6.10 (d, J = 8.0 Hz, 1H), 6-methylthieno[2,3-b]pyridine-2- 5.91 (s, 1H), 4.82-4.81 (m, 1H), 4.47- carboxamide 4.37 (m, 3H), 4.28-4.25 (m, 1H), 4.15- 4.13 (m, 1H), 3.81-3.77 (m, 1H), 3.56- 3.43 (m, 3H), 3.34-3.32 (m, 1H), 2.87- 2.83 (m, 3H), 2.59 (s, 3H), 2.11 (br s, 2H). 260 3-amino-N-[(3R)-7-[(25,4R)-4- 468 (DMSO-d6 400 MHz) δ (ppm): 8.33 (d, ++++ ++++ amino-2- J = 8.4 Hz, 1H), 7.49 (br s, 1H), 7.31 (d, (methoxymethyl)pyrrolidin-1-yl]- J = 8.0 Hz, 1H), 7.22 (br s, 2H), 6.87 (d, 3,4-dihydro-2H-1-benzopyran-3- J = 8.0 Hz, 1H), 6.16 (d, J = 8.4 Hz, 1H), yl]-6-methylthieno[2,3- 5.96 (s, 1H), 4.32-4.25 (m, 1H), 4.16- b]pyridine-2-carboxamide 4.13 (m, 1H), 3.82-3.77 (m, 2H), 3.62- 3.52 (m, 1H), 3.48-3.44 (m, 1H), 3.38- 3.20 (m, 5H), 2.89-2.78 (m, 2H), 2.66- 2.62 (m, 1H), 2.59 (s, 3H), 2.10-1.90 (m, 3H), 1.73-1.65 (m, 1H). 261 3-amino-N-[(3R)-7-[(2R,4S)-4- 468 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, amino-2- J = 8.4 Hz, 1H), 7.51 (br s, 1H), 7.32 (d, (methoxymethyl)pyrrolidin-1-yl]- J = 8.0 Hz, 1H), 7.22 (br s, 2H), 6.88 (d, ++++ +++ 3,4-dihydro-2H-1-benzopyran-3- J = 8.4 Hz, 1H), 6.17-6.14 (m, 1H), 5.96 yl]-6-methylthieno[2,3- (d, J = 1.6 Hz, 1H), 4.30-4.25 (m, 1H), b]pyridine-2-carboxamide 4.15-4.12 (m, 1H), 3.82-3.77 (m, 2H), 3.62-3.58 (m, 1H), 3.47-3.43 (m, 1H), 3.38-3.35 (m, 1H), 3.27 (s, 3H), 3.23- 3.19 (m, 1H), 2.86-2.81 (m, 2H), 2.65- 2.51 (m, 4H), 2.06-2.01 (m, 1H), 1.73- 1.64 (m, 3H). 262 3-amino-N-[(3R)-7-[(2R,4R)-4- 468 (DMSO-d6, 400 MHz) δ (ppm): 8.32 (d, ++++ ++ amino-2- J = 8.4 Hz, 1H), 7.49 (br s, 1H), 7.31 (d, (methoxymethyl)pyrrolidin-1-yl]- J = 8.0 Hz, 1H), 7.21 (br s, 2H), 6.87 (d, 3,4-dihydro-2H-1-benzopyran-3- J = 8.4 Hz, 1H), 6.19-6.17 (m, 1H), 5.99 yl]-6-methylthieno[2,3- (s, 1H), 4.28-4.25 (m, 1H), 4.15-4.12 (m, b]pyridine-2-carboxamide 1H), 3.82-3.75 (m, 2H), 3.53-3.51 (m, 3H), 3.27-3.24 (m, 4H), 3.04-3.01 (m, 1H), 2.85-2.81 (m, 2H), 2.58 (s, 3H), 2.20-2.17 (m, 1H), 2.10-1.90 (br s, 1H), 1.74-1.69 (m, 1H). 263 3-amino-N-[(3R)-7-[(2S,4S)-4- 468 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, ++++ +++ amino-2- J = 8.4 Hz, 1H), 7.50 (br s, 1H), 7.32 (d, (methoxymethyl)pyrrolidin-1-yl]- J = 8.0 Hz, 1H), 7.21 (br s, 2H), 6.87 (d, 3,4-dihydro-2H-1-benzopyran-3- J = 8.4 Hz, 1H), 6. 19 (d, J = 8.4 Hz, 1H), yl]-6-methylthieno[2,3- 6.02 (s, 1H), 4.32-4.21 (m, 1H), 4.16- b]pyridine-2-carboxamide 4.13 (m, 1H), 3.81-3.76 (m, 2H), 3.52- 3.48 (m, 3H), 3.32-3.25 (m, 4H), 3.05- 3.03 (m, 1H), 2.89-2.78 (m, 2H), 2.59 (s, 3H), 2.23-2.16 (m, 2H), 1.73-1.70 (m, 1H). 264 (6aS,7aR)-N-[(3R)-6-cyano-7- 475 (DMSO-d6 400 MHz) δ (ppm): 8.27 (d, ++++ ++++ {3,8-diazabicyclo[3.2.1]octan-3- J = 2.4 Hz, 1H), 8.14 (d, J = 6.4 Hz, 1H), yl}-5-fluoro-3,4-dihydro-2H-1- 7.84 (d, J = 2.4 Hz, 1H), 6.63 (br s, 1H), benzopyran-3-yl]- 6.32 (s, 1H), 4.31-4.24 (m, 2H), 4.10- 5H,6H,6aH,7H,7aH- 4.06 (m, 1H), 3.63-3.60 (m, 2H), 3.38- cyclopropa[c]1,8-naphthyridine- 3.30 (m, 4H), 3.00-2.68 (m, 3H), 2.77- 2-carboxamide 2.68 (m, 1H), 1.98-1.91(m, 3H), 1.76- 1.67 (m, 3H), 0.96-0.90 (m, 2H). 265 (6aR,7aS)-N-[(3R)-6-cyano-7- 475 (DMSO-d6 400 MHz) δ (ppm): 8.27 (d, +++ ++ {3,8-diazabicyclo[3.2.1]octan-3- J = 2.0 Hz, 1H), 8.14 (d, J = 6.4 Hz, 1H), yl}-5-fluoro-3,4-dihydro-2H-1- 7.84 (d, J = 2.0 Hz, 1H), 6.63 (br s, 1H), benzopyran-3-yl]- 6.28 (s, 1H), 4.29-4.23 (m, 2H), 4.10- 5H,6H,6aH,7H,7aH- 3.26 (m, 4H), 2.99-2.87 (m, 3H), 2.76- cyclopropa[c]1,8-naphthyridine- 2.70 (m, 1H), 1.96-1.85 (m, 3H), 1.74- 2-carboxamide 1.63 (m, 3H), 0.96-0.90 (m, 2H). 266 7-amino-N-[(6S)-2-[(3S,4S)-3- 496 (DMSO-d6, 400 MHz) δ (ppm): 8.65 (s, ++ + acetamido-4-methoxypyrrolidin- 1H), 8.13 (d, J = 7.2 Hz, 1H), 7.81 (d, J = 1-yl]-5,6,7,8-tetrahydroquinolin- 7.6 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 6-yl]-3-methylthieno[2,3- 6.92 (s, 2H), 6.28 (d, J = 8.4 Hz, 1H), b]pyrazine-6-carboxamide 4.26 (br s, 1H), 4.15 (br s, 1H), 3.81- 3.80 (m, 1H), 3.60-3.54 (m, 2H), 3.39- 3.28(m, 5 H), 2.86-2.70 (m, 4 H), 2.66 (s, 3 H), 2.04-2.00 (m, 1 H), 1.90-1.83 (m, 1H), 1.82 (s, 3H). 267 3-amino-N-[(2S)-6-[(3S,4R)-3- 466 (DMSO-d6 400 MHz) δ (ppm): 8.30 (d, +++ ++ amino-4-ethoxypyrrolidin-1-yl]- J = 8.4 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 1,2,3,4-tetrahydronaphthalen-2- 7.31 (d, J = 8.0 Hz, 1H), 7.15 (br s, 2H), yl]-6-methylthieno[2,3- 6.86 (d, J = 8.4 Hz, 1H), 6.29 (dd, J = b]pyridine-2-carboxamide 8.4, 2.0 Hz, 1H), 6.20 (s, 1H), 4.14-4.07 (m, 1H), 3.87-3.85 (m, 1H), 3.60-3.47 (m, 3H), 3.38-3.33 (m, 2H), 3.24-3.21 (m, 1H), 2.89-2.72 (m, 5H), 2.59 (s, 3H), 1.97-1.95 (m, 1H), 1.77 (br s, 2H), 1.74- 1.68 (m, 1H), 1.15 (t, J = 7.2 Hz, 3H). 268 3-amino-N-[(2S)-6-[(3R,4S)-3- 466 (DMSO-d6, 400 MHz) δ (ppm): 8.30 (d, +++ + amino-4-ethoxypyrrolidin-1-yl]- J = 8.4 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 1,2,3,4-tetrahydronaphthalen-2- 7.31 (d, J = 8.0 Hz, 1H), 7.15 (br s, 2H), yl]-6-methylthieno[2,3- 6.86 (d, J = 8.4 Hz, 1H), 6.29 (dd, J = b]pyridine-2-carboxamide 8.8, 2.0 Hz, 1H), 6.20 (s, 1H), 4.13-4.07 (m, 1H), 3.86-3.85 (m, 1H), 3.60-3.47 (m, 3H), 3.38-3.33 (m, 2H), 3.24-3.21 (m, 1H), 2.88-2.68 (m, 5H), 2.59 (s, 3H), 1.97-1.95 (m, 1H), 1.76-1.74 (m, 1H), 1.58 (br s, 2H), 1.15 (t, J = 7.2 Hz, 3H). 269 3-amino-N-[(6S)-2-[(3S,4R)-3- 453 (DMSO-d6, 400 MHz) δ (ppm): 8.31 (d, +++ + amino-4-methoxypyrrolidin-1- J = 8.0 Hz, 1H), 7.57 (br s, 1H), 7.31 (d, yl]-5,6,7,8-tetrahydroquinolin-6- J = 8.0 Hz, 1H), 7.20-7.16 (m, 3H), 6.21 yl]-6-methylthieno[2,3- (d, J = 8.4 Hz, 1H), 4.15-4.11 (m, 1H), b]pyridine-2-carboxamide 3.73-3.72 (m, 1H), 3.53-3.33 (m, 7H), 3.00-2.94 (m, 1H), 2.82-2.68 (m, 4H), 2.59 (s, 3H), 2.02-1.98 (m, 1H), 1.90- 1.82 (m, 1H), 1.62 (br s, 2H). 270 3-amino-N-[(6S)-2-[(3R,4S)-3- 453 (DMSO-d6, 400 MHz) δ (ppm): 8.31 (d, +++ + amino-4-methoxypyrrolidin-1- J = 8.4 Hz, 1H), 7.57 (br s, 1H), 7.31 (d, yl]-5,6,7,8-tetrahydroquinolin-6- J = 8.4 Hz, 1H), 7.20-7.16 (m, 3H), 6.21 yl]-6-methylthieno[2,3- (d, J = 8.8 Hz, 1H), 4.16-4.11 (m, 1H), b]pyridine-2-carboxamide 3.75-3.74 (m, 1H), 3.52-3.34 (m, 7H), 3.02-2.96 (m, 1H), 2.82-2.68 (m, 4H), 2.59 (s, 3H), 2.08-1.79 (m, 4H). 271 3-amino-N-[(6S)-2-[(3S,4S)-3- 482 (DMSO-d6, 400 MHz) δ (ppm): 8.30 (d, + amino-4-(propan-2- J = 8.0 Hz, 1H), 8.06 (s, 1H), 7.61 (d, J = yloxy)pyrrolidin-1-yl]-5,6,7,8- 7.6 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), tetrahydroquinazolin-6-yl]-6- 7.16 (s, 2H), 4.12 (br s, 1H), 3.77-3.69 methylthieno[2,3-b]pyridine-2- (m, 3H), 3.56-3.52 (m, 1 H), 3.37-3.32 carboxamide (m, 2H), 3.25-3.22 (m, 1H), 2.84-2.64 (m, 4H), 2.59 (s, 3 H), 2.04-1.98 (m, 1 H), 1.88-1.83 (m, 1H), 1.68 (br s, 2H), 1.11-1.10 (m, 6H). 272 3-amino-N-[(6R)-2-[(3S,4S)-3- 482 (DMSO-d6, 400 MHz) δ (ppm): 8.30 (d, ++ amino-4-(propan-2- J = 8.0 Hz, 1H), 8.06 (s, 1H), 7.61 (d, J = yloxy)pyrrolidin-1-yl]-5,6,7,8- 8.0 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), tetrahydroquinazolin-6-yl]-6- 7.16 (s, 2H), 4.12 (br, 1H), 3.79-3.70 (m, methylthieno[2,3-b]pyridine-2- 3H), 3.57-3.53 (m, 1 H), 3.37-3.32 (m, carboxamide 2H), 3.25-3.22 (m, 1H), 2.84-2.61 (m, 4H), 2.59 (s, 3 H), 2.01-1.83 (m, 4 H), 1.12-1.08 (m, 6H). 273 3-amino-N-[(6S)-2-[(3S,4S)-3- 468 (DMSO-d6, 400 MHz) δ (ppm): 8.07 (s, + amino-4-methoxypyrrolidin-1- 1H), 7.65 (br s, 1H), 7.04 (s, 1H), 6.83 yl]-5,6,7,8-tetrahydroquinazolin- (br s, 2H), 4.15-4.12 (m, 1H), 3.69-3.61 6-yl]-4,6-dimethylthieno[2,3- (m, 2H), 3.54-3.43 (m, 3H), 3.29-3.27 b]pyridine-2-carboxamide (m, 5H), 2.83-2.62 (m, 7H), 2.03-1.97 (m, 1H), 1.95-1.82 (m, 1H), 1.75-1.65 (m, 2H). 274 3-amino-N-[(6R)-2-[(3S,4S)-3- 468 (DMSO-d6, 400 MHz) δ (ppm): 8.06 (s, ++ amino-4-methoxypyrrolidin-1- 1H), 7.65 (br s, 1H), 7.04 (s, 1H), 6.82 yl]-5,6,7,8-tetrahydroquinazolin- (br s, 2H), 4.16-4.12 (m, 1H), 3.69-3.61 6-yl]-4,6-dimethylthieno[2,3- (m, 2H), 3.54-3.42 (m, 3H), 3.29-3.26 b]pyridine-2-carboxamide (m, 5H), 2.83-2.72 (m, 6H), 2.68-2.61 (m, 1H), 2.03-1.97 (m, 1H), 1.95-1.82 (m, 1H), 1.75-1.65 (m, 2H). 275 3-amino-N-[(3R)-7-[(3R,4R)-3- 482 (DMSO-d6, 400 MHz) δ (ppm): 7.52 (d, ++++ ++ amino-4- J = 7.6 Hz, 1H), 7.05 (s, 1H), 6.94-6.86 (methoxymethyl)pyrrolidin-1-yl]- (m, 2H), 6.07 (d, J = 6.4 Hz, 1H), 5.87 3,4-dihydro-2H-1-benzopyran-3- (s, 1H), 4.27 (br s, 1H), 4.15-4.12 (m, yl]-4,6-dimethylthieno[2,3- 1H), 3.81-3.78 (m, 1H), 3.62-3.49 (m, b]pyridine-2-carboxamide 2H), 3.40-3.33 (m, 2H), 3.28 (s, 3H), 3.25-3.20 (m, 1H), 3.09-3.05 (m, 1H), 2.96-2.93 (m, 1H), 2.89-2.81 (m, 2H), 2.73 (s, 3H), 2.51 (s, 3H), 2.44-2.37 (m, 1H), 1.53 (br s, 2H). 276 3-amino-N-[(3R)-7-[(3S,4S)-3- 482 (DMSO-d6, 400 MHz) δ (ppm): 7.52 (d, ++++ +++ amino-4- J = 7.6 Hz, 1H), 7.07 (s, 1H), 6.86 (s, (methoxymethyl)pyrrolidin-1-yl]- 3H), 6.07 (d, J = 6.8 Hz, 1H), 5.87 (s, 3,4-dihydro-2H-1-benzopyran-3- 1H), 4.27 (br s, 1H), 4.15-4.12 (m, 1H), yl]-4,6-dimethylthieno[2,3- 3.81-3.76 (m, 1H), 3.60-3.50 (m, 2H), b]pyridine-2-carboxamide 3.40-3.33 (m, 2H), 3.28 (s, 3H), 3.25- 3.21 (m, 1H), 3.09-3.04 (m, 1H), 2.98- 2.93 (m, 1H), 2.89-2.77 (m, 2H), 2.73 (s, 3H), 2.51 (s, 3H), 2.46-2.42 (m, 1H), 1.54 (br s, 2H). 277 3-amino-N-[(3R)-7-[(3R,4R)-3- 518 (DMSO-d6, 400 MHz) δ (ppm): 7.66 (br ++++ ++ amino-4- s, 1H), 7.04 (s, 1H), 6.87 (br s, 2H), (methoxymethyl)pyrrolidin-1-yl]- 6.10-6.06 (m, 1H), 4.29-4.26 (m, 2H), 5,8-difluoro-3,4-dihydro-2H-1- 3.93-3.91 (m, 1H), 3.55-3.50 (m, 5H), benzopyran-3-yl]-4,6- 3.32-3.27 (m, 4H), 3.12-3.08 (m, 1H), dimethylthieno[2,3-b]pyridine-2- 2.89-2.87 (m, 1H), 2.79-2.62 (m, 4H), carboxamide 2.54-2.52 (m, 3H), 2.38-2.36 (m, 1H), 2.15-2.07 (m, 1H), 1.88-1.70 (m, 2H). 278 3-amino-N-[(3R)-7-[(3S,4S)-3- 518 (DMSO-d6, 400 MHz) δ (ppm): 7.65 (br ++++ +++ amino-4- s, 1H), 7.04 (s, 1H), 6.87 (br s, 2H), (methoxymethyl)pyrrolidin-1-yl]- 6.10-6.06 (m, 1H), 4.29-4.24 (m, 2H), 5,8-difluoro-3,4-dihydro-2H-1- 3.93-3.89 (m, 1H) 3.58-3.49 (m, 3H) benzopyran-3-yl]-4,6- 3.40-3.36 (m, 2H), 3.29-3.23 (m, 4H), dimethylthieno[2,3-b]pyridine-2- 3.08-3.06 (m, 1H), 2.89-2.87 (m, 1H), carboxamide 2.79-2.67 (m, 4H), 2.54-2.52 (m, 3H), 2.39-2.33 (m, 1H), 1.88-1.70 (m, 1H). 279 7-amino-N-[(6S)-2-[(3S,4S)-4- 468 (DMSO-d6, 400 MHz) δ (ppm): 8.65 (s, ++ + amino-3-methoxy-3- 1H), 7.82 (br s, 1H), 7.18 (d, J = 8.0 Hz, methylpyrrolidin-1-yl]-5,6,7,8- 1H), 6.92 (br s, 2H), 6.19 (d, J = 8.4 Hz, tetrahydroquinolin-6-yl]-3- 1H), 4.18-4.14 (m, 1H), 3.59-3.55 (m, methylthieno[2,3-b]pyrazine-6- 1 H), 3.50-3.47 (m, 1H), 3.32-3.29 (m, carboxamide 2H), 3.17 (s, 3H), 3.07-3.04 (m, 1H), 2.84-2.73 (m, 4H), 2.66 (s, 3H), 2.03- 2.00 (m, 1H), 1.89-1.83 (m, 1H), 1.65 (br s, 2H), 1.23 (s, 3H). 280 7-amino-N-[(6S)-2-[(3R,4R)-4- 468 (DMSO-d6, 400 MHz) δ (ppm): 8.65 (s, ++ + amino-3-methoxy-3- 1H), 7.81 (br s, 1H), 7.18 (d, J = 8.4 Hz, methylpyrrolidin-1-yl]-5,6,7,8- 1H), 6.92 (br s, 2H), 6.19 (d, J = 8.4 Hz, tetrahydroquinolin-6-yl]-3- 1H), 4.17-4.13 (m, 1H), 3.60-3.56 (m, methylthieno[2,3-b]pyrazine-6- 1H), 3.47-3.45 (m, 1H), 3.32-3.29 (m, carboxamide 2H), 3.17 (s, 3H), 3.07-3.03 (m, 1H), 2.84-2.68 (m, 4H), 2.66 (s, 3H), 2.03- 2.00 (m, 1H), 1.88-1.83 (m, 1H), 1.61 (br s, 2H), 1.23 (s, 3H). 281 3-amino-N-[(3R)-7-[(3S,4S)-4- 468 (DMSO-d6, 400 MHz) δ (ppm): 8.32 (d, ++++ ++ amino-3-methoxy-3- J = 8.0 Hz, 1H), 7.48 (br s, 1H), 7.31 (d, methylpyrrolidin-1-yl]-3,4- J = 8.4 Hz, 1H), 7.21 (br s, 2H), 6.86 (d, dihydro-2H-1-benzopyran-3-yl]- J = 8.4 Hz, 1H), 6.06 (d, J = 8.4 Hz, 1H), 6-methylthieno[2,3-b]pyridine-2- 5.87 (s, 1H), 4.30-4.26 (m, 1H), 4.15- carboxamide 4.13 (m, 1H), 3.81-3.76 (m, 1H), 3.47- 3.43 (m, 1H), 3.32-3.24 (m, 2H), 3.17- 3.15 (m, 4H), 2.89-2.78 (m, 3H), 2.59 (s, 3H), 1.63 (br s, 2H), 1.23 (s, 3H). 282 3-amino-N-[(3R)-7-[(3R,4R)-4- 468 (DMSO-d6, 400 MHz) δ (ppm): 8.32 (d, ++++ ++ amino-3-methoxy-3- J = 8.0 Hz, 1H), 7.48 (br s, 1H), 7.31 (d, methylpyrrolidin-1-yl]-3,4- J = 8.0 Hz, 1H), 7.21 (br s, 2H), 6.86 (d, dihydro-2H-1-benzopyran-3-yl]- J = 8.4 Hz, 1H), 6.08-6.05 (m, 1H), 5.87 6-methylthieno[2,3-b]pyridine-2- (s, 1H), 4.30-4.26 (m, 1H), 4.15-4.12 (m, carboxamide 1H), 3.81-3.76 (m, 1H), 3.47-3.43 (m, 1H), 3.32-3.24 (m, 2H), 3.17-3.15 (m, 4H), 2.89-2.77 (m, 3H), 2.59 (s, 3H), 1.58 (br s, 2H), 1.23 (s, 3H). 283 3-amino-N-[(3R)-7-[(2S,3R,4S)- 468 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, ++++ +++ 4-amino-3-methoxy-2- J = 8.4 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), methylpyrrolidin-1-yl]-3,4- 7.32 (d, J = 8.4 Hz, 1H), 7.21 (br s, 2H), dihydro-2H-1-benzopyran-3-yl]- 6.87 (d, J = 8.0 Hz, 1H), 6.14 (d, J = 8.4 6-methylthieno[2,3-b]pyridine-2- Hz, 1H), 5.95 (s, 1H), 4.31-4.26 (m, carboxamide 1H), 4.16-4.12 (m, 1H), 3.81-3.77 (m, 1H), 3.66-3.61 (m, 1H), 3.37-3.32 (m, 6H), 3.09-3.05 (m, 1H), 2.89-2.78 (m, 2H), 2.59 (s, 3H), 1.83 (br s, 2H), 1.29 (d, J = 8.0 Hz, 3H). 284 3-amino-N-[(3R)-7-[(2R,3S,4R)- 468 (DMSO-d6 400 MHz) δ (ppm): 8.33 (d, ++++ +++ 4-amino-3-methoxy-2- J = 8.0 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), methylpyrrolidin-1-yl]-3,4- 7.32 (d, J = 8.0 Hz, 1H), 7.21 (br s, 2H), dihydro-2H-1-benzopyran-3-yl]- 6.87 (d, J = 8.4 Hz, 1H), 6.14 (d, J = 8.4 6-methylthieno[2,3-b]pyridine-2- Hz, 1H), 5.95 (s, 1H), 4.30-4.26 (m, carboxamide 1H), 4.16-4.13 (m, 1H), 3.82-3.77 (m, 1H), 3.66-3.61 (m, 1H), 3.42-3.32 (m, 6H), 3.09-3.06 (m, 1H), 2.90-2.78 (m, 2H), 2.59 (s, 3H), 1.88 (br s, 2H), 1.29 (d, J = 8.0 Hz, 3H). 285 3-amino-N-[(6S)-2-[(3S,4S)-3- 493 (DMSO-d6, 400 MHz) δ (ppm): 8.31 (d, +++ + amino-4-cyclobutoxypyrrolidin- J = 8.4 Hz, 1H), 7.56 (br s, 1H), 7.31 (d, 1-yl]-5,6,7,8-tetrahydroquinolin- J = 8.0 Hz, 1H), 7.20-7.15 (m, 3H), 6.22 6-yl]-6-methylthieno[2,3- (d, J = 8.4 Hz, 1H), 4.14-4.03 (m, 2H), b]pyridine-2-carboxamide 3.72-3.69 (m, 1H), 3.62-3.58 (m, 1H), 3.50-3.46 (m, 1H), 3.30-3.28 (m, 2H), 3.11-3.09 (m, 1H), 2.81-2.68 (m, 4H), 2.58 (s, 3H), 2.23-2.16 (m, 2H), 2.02- 1.99 (m, 1H), 1.90-1.82 (m, 3H), 1.65- 1.55 (m, 1H), 1.51-1.41 (m, 1H). 286 3-amino-N-[(3R)-7-[(3S,4S)-3- 469 (DMSO-d6, 400 MHz) δ (ppm): 7.56 (d, +++ + amino-4-methoxypyrrolidin-1- J = 7.6 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), yl]-2H,3H,4H-pyrano[2,3- 7.05 (s, 1H), 6.86 (br s, 2H), 6.02 (d, J = b]pyridin-3-yl]-4,6- 8.4 Hz, 1H), 4.30-4.26 (m, 1H), 4.22- dimethylthieno[2,3-b]pyridine-2- 4.19 (m, 1H), 3.97-3.92 (m, 1H), 3.62- carboxamide 3.55 (m, 2H), 3.42-3.40 (m, 2H), 3.32 (s, 3H), 3.30-3.29 (m, 4H), 3.11-3.09 (m, 1H), 2.84-2.81 (m, 2H), 2.73 (s, 3H), 1.68 (br s, 2H). 287 3-amino-N-[(3R)-7-[(3S,4S)-3- 483 (DMSO-d6, 400 MHz) δ (ppm): 8.31 (d, ++ + amino-4-(propan-2- J = 8.4 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), yloxy)pyrrolidin-1-yl]-2H,3H,4H- 7.31 (d, J = 8.0 Hz, 1H), 7.20-7.15 (m, pyrano[2,3-b]pyridin-3-yl]-6- 3H), 6.22 (d, J = 8.4 Hz, 1H), 4.14-4.03 methylthieno[2,3-b]pyridine-2- (m, 2H), 3.71-3.69 (m, 1H), 3.62-3.59 carboxamide (m, 1H), 3.50-3.45 (m, 1H), 3.30-3.28 (m, 2H), 3.14-3.10 (m, 1H), 2.81-2.68 (m, 4H), 2.58 (s, 3H), 2.21-2.17 (m, 2H), 2.07-1.95(m, 1H), 1.90-1.82 (m, 4H), 1.68-1.60 (m, 1H), 1.51-1.44 (m, 1H). 288 3-amino-N-[(3R)-7-[(3R)-3- 424 (DMSO-d6 400 MHz) δ (ppm): 8.33 (d, ++++ ++ aminopyrrolidin-1-yl]-3,4- J = 8.4 Hz, 1H), 7.48 (br s, 1H), 7.32 (d, dihydro-2H-1-benzopyran-3-yl]- J = 8.4 Hz, 1H), 7.21 (br s, 2H), 6.86 (d, 6-methylthieno[2,3-b]pyridine-2- J = 8.4 Hz, 1H), 6.10 (d, J = 8.0 Hz, 1H), carboxamide 5.90 (s, 1H), 4.30-4.26 (m, 1H) 4.16- 4.12 (m, 1H), 3.82-3.77 (m, 1H), 3.55- 3.53 (m, 1H), 3.30-3.25 (m, 2H), 3.19- 3.13 (m, 1H), 2.89-2.80 (m, 3H), 2.59 (s, 3H), 2.10-1.90 (m, 2H), 1.72-1.64 (m, 2H). 289 N-[(3R)-7-[(3aR,6aS)-3a- 480 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, J = ++++ methoxy-octahydropyrrolo[2,3- 8.0 Hz, 1H), 7.52 (br s, 1H), 7.32 (d, J = c]pyrrol-5-yl]-3,4-dihydro-2H-1- 8.4 Hz, 1H), 7.23 (br s, 2H), 6.89 (d, J = benzopyran-3-yl]-3-amino-6- 8.4 Hz, 1H), 6.24-6.21 (m, 1H), 6.05 methylthieno[2,3-b]pyridine-2- (s, 1H), 4.32-4.28 (m, 1H), 4.16-4.13 (m, carboxamide 1H), 3.82-3.77 (m, 1H), 3.63-3.61 (m, 1H), 3.43-3.23 (m, 6H), 2.98-2.83 (m, 5H), 2.59 (s, 3H), 2.04-2.00 (m, 1H), 1.85-1.81 (m, 1H). 290 N-[(3R )-7-[(3aS,6aR)-3a- 480 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, ++++ methoxy-octahydropyrrolo[2,3- J = 8.0 Hz, 1H), 7.52 (br s, 1H), 7.32 (d, c]pyrrol-5-yl]-3,4-dihydro-2H-1- J = 8.4 Hz, 1H), 7.23 (br s, 2H), 6.89 (d, benzopyran-3-yl]-3-amino-6- J = 8.4 Hz, 1H), 6.24-6.21 (m, 1H), 6.05 methylthieno[2,3-b]pyridine-2- (s, 1H), 4.32-4.28 (m, 1H), 4.16-4.14 (m, carboxamide 1H), 3.82-3.77 (m, 1H), 3.62-3.61 (m, 1H), 3.44-3.23 (m, 6H), 3.00-2.83 (m, 5H), 2.59 (s, 3H), 2.03-2.00 (m, 1H), 1.84-1.81 (m, 1H). 291 N-[(3R)-7-[(3aS,6aS)-3a- 480 (DMSO-d6, 400 MHz) δ (ppm): 8.32 (d, ++++ ++ methoxy-octahydropyrrolo[3,4- J = 8.0 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), c]pyrrol-2-yl]-3,4-dihydro-2H-1- 7.31 (d, J = 8.0 Hz, 1H), 7.22 (s, 2H), benzopyran-3-yl]-3-amino-6- 6.90 (d, J = 8.4 Hz, 1H), 6.27-6.25 (m, methylthieno[2,3-b]pyridine-2- 1H), 6.07 (s, 1H), 4.29 (br s, 1H), 4.16- carboxamide 4.14 (m, 1H), 3.83-3.78 (m, 1H), 3.52- 3.44 (m, 2H), 3.22-3.20 (m, 4H), 3.14- 3.10 (m, 1H), 3.02-2.93 (m, 1H), 2.92- 2.80 (m, 4H), 2.68-2.63 (m, 2H), 2.59 (s, 3H). 292 N-[(3R)-7-[(3aR,6aR)-3a- 480 (DMSO-d6, 400 MHz) δ (ppm): 8.32 (d, ++++ ++ methoxy-octahydropyrrolo[3,4- J = 8.0 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), c]pyrrol-2-yl]-3,4-dihydro-2H-1- 7.31 (d, J = 8.4 Hz, 1H), 7.22 (m, 2H), benzopyran-3-yl]-3-amino-6- 6.90 (d, J = 8.4 Hz, 1H), 6.27-6.25 (m, methylthieno[2,3-b]pyridine-2- 1H), 6.07 (s, 1H), 4.28 (m, 1H), 4.16- carboxamide 4.13 (m, 1H), 3.82-3.78 (m, 1H), 3.52- 3.44 (m, 2H),3.22-3.20 (m, 4H), 3.14- 3.09 (m, 1H), 3.01-2.98 (m, 1H), 2.94- 2.80 (s, 4H), 2.68-2.58 (m, 5H). 293 3-amino-N-[(6S)-2-[(3S,4S)-3- 509 (DMSO-d6 400 MHz) δ (ppm): 8.14 (d, +++ + acetamido-4-methoxypyrrolidin- J = 6.8 Hz, 1H), 7.60 (br s, 1H), 722 (d, 1-yl]-5,6,7,8-tetrahydroquinolin- J = 8.4 Hz, 1H), 7.04 (br s, 1H), 6.82 (br 6-yl]-4,6-dimethylthieno[2,3- s, 2H), 6.28 (d, J = 8.4 Hz, 1H), 4.28- b]pyridine-2-carboxamide 4.24 (m, 1H), 4.15-4.11 (m, 1H), 3.83- 3.79 (m, 1H), 3.60-3.54 (m, 2H), 3.39- 3.27 (m, 5H), 2.83-2.73 (m, 7H), 2.51 (s, 3H), 2.02-1.91 (m, 1H), 1.88-1.82 (m, 4H). 294 3-amino-N-[(3R)-7-[(3R,4S)-3- 474 (DMSO-d6 400 MHz) δ (ppm): 8.32 (d, ++++ +++ amino-4- J = 8.4 Hz, 1H), 7.49 (br s, 1H), 7.31 (d, (difluoromethyl)pyrrolidin-1-yl]- J = 8.0 Hz, 7.21 (br s, 2H), 6.89 (d, 3,4-dihydro-2H-1-benzopyran-3- J = 8.0 Hz, 1H), 6.20-6.13 (m, 2H), 5.94 yl]-6-methylthieno[2,3- (d, J = 2.4 Hz, 1H), 4.30-4.26 (m, 1H), b]pyridine-2-carboxamide 4.16-4.13 (m, 1H), 3.82-3.77 (m, 1H), 3.51-3.47(m, 2H), 3.41-3.33 (m, 2H), 3.25-3.20 (m, 1H), 2.90-2.82 (m, 3H), 2.58 (s, 3H), 1.88 (br s, 2H). 295 3-amino-N-[(3R)-7-[(3S,4R)-3- 474 (DMSO-d6, 400 MHz) δ (ppm): 8.32 (d, ++++ +++ amino-4- J = 8.4 Hz, 1H), 7.49 (br s, 1H), 7.31 (d, (difluoromethyl)pyrrolidin-1-yl]- J = 8.4 Hz, 1H), 7.21 (br s, 2H), 6.90 (d, 3,4-dihydro-2H-1-benzopyran-3- J = 8.0 Hz, 1H), 6.20-6.04 (m, 2H), 5.94 yl]-6-methylthieno[2,3- (d, J = 2.0 Hz, 1H), 4.30-4.26 (m, 1H), b]pyridine-2-carboxamide 4.16-4.13 (m, 1H), 3.82-3.77 (m, 1H), 3.51-3.32 (m, 4H), 3.24-3.20 (m, 1H), 2.90-2.83 (m, 3H), 2.58 (s, 3H), 1.91 (br s, 2H). 296 3-amino-N-[(6S)-2-[(3R,4R)-3- 481 (MeOH-d4, 400 MHz) δ (ppm): 7.25 (d, +++ + amino-4- J = 8.4 Hz, 1H), 7.07 (s, 1H), 6.32 (d, J = (methoxymethyl)pyrrolidi n-1-yl]- 8.4 Hz, 1H), 4.29-4.24 (m, 1H), 3.69- 5,6,7,8-tetrahydroquinolin-6-yl]- 3.55 (m, 5H), 3.43-3.34 (m, 5H), 2.97- 4,6-dimethylthieno[2,3- 2.92 (m, 3H), 2.81-2.61 (m, 5H), 2.59 (s, b]pyridine-2-carboxamide- 3H), 2.18-2.15 (m, 1H), 1.99-1.90 (m, 1H). 297 3-amino-N-[(6S)-2-[(3S,4S)-3- 481 (MeOH-d4, 400 MHz) δ (ppm): 7.26 (d, ++++ ++ amino-4- J = 8.4 Hz, 1H), 7.07 (s, 1H), 6.32 (d, J = (methoxymethyl)pyrrolidin-1-yl]- 8.8 Hz, 1H), 4.30-4.24 (m, 1H), 3.69- 5,6,7,8-tetrahydroquinolin-6-yl]- 3.63 (m, 3H), 3.60-3.55 (m, 2H), 3.43- 4,6-dimethylthieno[2,3- 3.35 (m, 5H), 2.97-2.92 (m, 3H), 2.81- b]pyridine-2-carboxamide 2.72 (m, 4H), 2.66-2.61 (m, 1H), 2.58 (s, 3H), 2.18-2.15 (m, 1H), 1.97-1.89 (m, 1H). 298 7-amino-N-[(6S)-2-[(3R,4R)-3- 468 (DMSO-d6 400 MHz) δ (ppm): 8.65 (s, ++ + amino-4- 1H), 7.81 (br s, 1H), 7.18 (d, J = 8.8 Hz, (methoxymethyl)pyrrolidin-1-yl]- 1H), 6.92 (br s, 2H), 6.20 (d, J = 8.4 Hz, 5,6,7,8-tetrahydroquinolin-6-yl]- 1H), 4.16-4.11 (m, 1H), 3.60-3.37 (m, 3-methylthieno[2,3-b]pyrazine- 5H), 3.28 (s, 3H), 3.22-3.17 (m, 2H), 6-carboxamide 2.83-2.72 (m, 4H), 2.65 (s, 3H), 2.42- 2.38 (m, 1H), 2.02-1.87 (m, 2H), 1.58 (br s, 2H). 299 7-amino-N-[(6S)-2-[(3S,4S)-3- 468 (DMSO-d6, 400 MHz) δ (ppm): 8.65 (s, +++ ++ amino-4- 1H), 7.81 (br s, 1H), 7.18 (d, J = 8.4 Hz, (methoxymethyl)pyrrolidin-1-yl]- 1H), 6.92 (br s, 2H), 6.20 (d, J = 8.4 Hz, 5,6,7,8-tetrahydroquinolin-6-yl]- 1H), 4.16-4.14 (m, 1H), 3.60-3.37 (m, 3-methylthieno[2,3-b]pyrazine- 5H), 3.28 (s, 3H), 3.21-3.16 (m, 2H), 6-carboxamide 2.83-2.72 (m, 4H), 2.65 (s, 3H), 2.43- 2.38 (m, 1H), 2.02-1.80 (m, 2H), 1.56 (br s, 2H). 300 3-amino-N-[(6S)-2-[(3R,4R)-3- 485 (MeOH-d4, 400 MHz) δ (ppm): 8.22 (d, ++ + amino-4- J = 8.4 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), (methoxymethyl)pyrrolidin-1-yl]- 7.05 (d, J = 13.6 Hz, 1H), 4.29-4.24 (m, 3-fluoro-5,6,7,8- 1H), 3.86-3.64 (m, 7H), 3.42 (s, 3H), tetrahydroquinolin-6-yl]-6- 2.98-2.87 (m, 3H), 2.80-2.67 (m, 2H), methylthieno[2,3-b]pyridine-2- 2.66 (s, 3H), 2.20-2.14 (m, 1H), 1.98- carboxamide 1.90 (m, 1H). 301 3-amino-N-[(6S)-2-[(3S,4S)-3- 485 (DMSO-d6 400 MHz) δ (ppm): 8.31 (d, + + amino-4- J = 8.4 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), (methoxymethyl)pyrrolidin-1-yl]- 7.31 (d, J = 8.4 Hz, 1H), 7.16-7.10 (m, 3-fluoro-5,6,7,8- 3H), 4.15-4.13 (m, 1H), 3.67-3.52 (m, tetrahydroquinolin-6-yl]-6- 4H), 3.42-3.36 (m, 3H), 3.28 (s, 3H), methylthieno[2,3-b]pyridine-2- 2.84-2.73 (m, 4H), 2.59 (s, 3H), 2.40- carboxamide 2.33 (m. 1H), 2.00-1.72 (m, 4H). 302 3-amino-N-[(6R)-2-[(3R,4R)-3- 485 (DMSO-d6 400 MHz) δ (ppm): 8.31 (d, +++ ++ amino-4- J = 8.0 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), (methoxymethyl)pyrrolidin-1-yl]- 7.31 (d, J = 8.4 Hz, 1H), 7.16-7.10 (m, 3-fluoro-5,6,7,8- 3H), 4.15-4.12 (m, 1H), 3.65-3.52 (m, tetrahydroquinolin-6-yl]-6- 4H), 3.41-3.35 (m, 3H), 3.28 (s, 3H), methylthieno[2,3-b]pyridine-2- 2.83-2.73 (m, 4H), 2.59 (s, 3H), 2.40- carboxamide 2.33 (m. 1H), 2.03-1.72 (m, 4H). 303 3-amino-N-[(6R)-2-[(3S,4S)-3- 485 (DMSO-d6 400 MHz) δ (ppm): 8.31 (d, ++ + amino-4- J = 8.4 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), (methoxymethyl)pyrrolidin-1-yl]- 7.31 (d, J = 8.4 Hz, 1H), 7.16-7.10 (m, 3-fluoro-5,6,7,8- 3H), 4.15-4.12 (m, 1H), 3.66-3.54 (m, tetrahydroquinolin-6-yl]-6- 4H), 3.42-3.35 (m, 3H), 3.28 (s, 3H), methylthieno[2,3-b]pyridine-2- 2.83-2.72 (m, 4H), 2.59 (s, 3H), 2.40- carboxamide 2.34 (m. 1H), 2.00-1.84 (m, 4H). 304 N-[(3R)-7-[(3aS,6aS)- 450 (DMSO-d6, 400 MHz) δ (ppm): 8.32 (d, ++++ ++ octahydropyrrolo[3,4-b]pyrrol-5- J = 8.4 Hz, 1H), 7.49 (br s, 1H), 7.32 (d, yl]-3,4-dihydro-2H-1- J = 8.0 Hz, 1H), 7.21 (br s, 2H), 6.87 (d, benzopyran-3-yl]-3-amino-6- J = 8.0 Hz, 1H), 6.20-6.18 (m, 1H), 6.00 methylthieno[2,3-b]pyridine-2- (s, 1H), 4.30-4.25 (m, 1H), 4.15-4.13 (m, carboxamide 1H), 3.81-3.76 (m, 2H), 3.28-3.26 (m, 2H), 3.01-2.93 (m, 2H), 2.86-2.79 (m, 5H), 2.59 (s, 3H), 1.85-1.80 (m, 1H), 1.58-1.56 (m, 1H). 305 N-[(3R)-7-[(3aR,6aR)- 450 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, ++++ +++ octahydropyrrolo[3,4-b]pyrrol-5- J = 8.0 Hz, 1H), 7.50 (br s, 1H), 7.32 (d, yl]-3,4-dihydro-2H-1- J = 8.0 Hz, 1H), 7.22 (br s, 2H), 6.87 (d, benzopyran-3-yl]-3-amino-6- J = 8.4 Hz, 1H), 6.19 (d, J = 6.8 Hz, 1H), methylthieno[2,3-b]pyridine-2- 6.00 (s, 1H), 4.29-4.25 (m, 1H), 4.15- carboxamide 4.13 (m, 1H), 3.83-3.76 (m, 2H), 3.29- 3.26 (m, 2H), 3.02-2.93 (m, 2H), 2.86- 2.79 (m, 5H), 2.59 (s, 3H), 1.86-1.80 (m, 1H), 1.59-1.56 (m, 1H). 306 3-amino-N-[(3R)-7-{2,6- 450 (DMSO-d6, 400 MHz) δ (ppm): 8.32 (d, ++++ ++ diazaspiro[3.4]octan-6-yl}-3,4- J = 8.4 Hz, 1H), 7.48 (br s, 1H), 7.31 (d, dihydro-2H-1-benzopyran-3-yl]- J = 8.4 Hz, 1H), 7.21 (br s, 2H), 6.87 (d, 6-methylthieno[2,3-b]pyridine-2- J = 8.0 Hz, 1H), 6.13-6.10 (m, 1H), 5.93 carboxamide (s, 1H), 4.32-4.23 (m, 1H), 4.15-4.12 (m, 1H), 3.81-3.76 (m, 2H), 3.48-3.38 (m, 3H), 3.31-3.27 (m, 2H), 3.19-3.13 (m, 2H), 2.89-2.78 (m, 2H), 2.58 (s, 3H), 2.12-2.08 (s, 2H). 307 3-amino-N-[(3R)-7-[(5S,9S)-9- 480 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, J = ++++ ++ amino-1-oxa-7- 8.0 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), azaspiro[4.4]nonan-7-yl]-3,4- 7.32 (d, J = 8.4 Hz, 1H), 7.21 (s, 2H), dihydro-2H-1-benzopyran-3-yl]- 6.86 (d, J = 8.4 Hz, 1H), 6.07 (d, J = 1.6 6-methylthieno[2,3-b]pyridine-2- Hz, 1H), 5.86 (s, 1H), 4.27-4.25 (m, 1H), carboxamide 4.15-4.13 (m, 1H), 3.81-3.72 (m, 3H), 3.43-3.40 (m, 1H), 3.19 (s, 1H), 3.09 (d, J = 9.6 Hz, 1H), 2.94 (d, J = 2.0 Hz, 1H), 2.92-2.79 (m, 2H), 2.59 (s, 3H), 2.22- 2.15 (m, 1H), 1.92-1.85 (m, 2H), 1.70- 1.63 (m, 3H). 308 3-amino-N-[(3R)-7-[(5R,9R)-9- 480 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, J = +++ ++ amino-1-oxa-7- 8.0 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), azaspiro[4.4]nonan-7-yl]-3,4- 7.32 (d, J = 8.4 Hz, 1H), 7.21 (s, 2H), dihydro-2H-1-benzopyran-3-yl]- 6.86 (d, J = 8.0 Hz, 1H), 6.07 (d, J = 1.6 6-methylthieno[2,3-b]pyridine-2- Hz, 1H), 5.86 (s, 1H), 4.27-4.25(m, 1H), carboxamide 4.15-4.12 (m, 1H), 3.81-3.72 (m, 3H), 3.43-3.40 (m, 1H), 3.19 (s, 1H), 3.09 (d, J = 9.6 Hz, 1H), 2.94 (d, J = 2.8 Hz, 1H), 2.92-2.79 (m, 2H), 2.59 (s, 3H), 2.22- 2.15 (m, 1H), 1.92-1.85 (m, 2H), 1.70- 1.63 (m, 3H). 309 3-amino-N-[(3R)-7-[(5S,9R)-9- 480 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, J = ++++ +++ amino-1-oxa-7- 8.4 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), azaspiro[4.4]nonan-7-yl]-3,4- 7.32 (d, J = 8.0 Hz, 1H), 7.21 (s, 2H), dihydro-2H-1-benzopyran-3-yl]- 6.86 (d, J = 8.4 Hz, 1H), 6.06-6.04(m, 6-methylthieno[2,3-b]pyridine-2- 1H), 5.85 (d, J = 1.6 Hz, 1H), 4.27-4.25 carboxamide (m, 1H), 4.15-4.12 (m, 1H), 3.84-3.76 (m, 3H), 3.39-3.32 (m, 1H), 3.27-3.18 (m, 3H), 2.82-2.77 (m, 3H), 2.59 (s, 3H), 1.98-1.89 (m, 4H), 2.56 (br,s, 2H). 310 3-amino-N-[(3R)-7-[(5R,9S)-9- 480 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, J = ++++ ++ amino-1-oxa-7- 8.4 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), azaspiro[4.4]nonan-7-yl]-3,4- 7.32 (d, J = 8.4 Hz, 1H), 7.21 (s, 2H), dihydro-2H-1-benzopyran-3-yl]- 6.86 (d, J = 8.4 Hz, 1H), 6.06-6.03(m, 6-methylthieno[2,3-b]pyridine-2- 1H), 5.85 (s, 1H), 4.29-4.27 (m, 1H), carboxamide 4.15-4.12 (m, 1H), 3.85-3.76 (m, 3H), 3.39-3.32 (m, 1H), 3.28-3.17 (m, 3H), 2.85-2.77 (m, 3H), 2.59 (s, 3H), 1.98- 1.89 (m, 4H), 2.56 (br,s, 1H). 311 3-amino-N-[(6S)-2-[(3S,4S)-3- 467 (DMSO-d6, 400 MHz) δ (ppm): 8.31 (d, +++ + methoxy-4- J = 8.4 Hz, 1H), 7.56 (br s, 1H), 7.31 (d, (methylamino)pyrrolidin-1-yl]- J = 8.0 Hz, 1H), 7.20-7.13 (m, 3H), 6.24 5,6,7,8-tetrahydroquinolin-6-yl]- (d, J = 7.6 Hz, 1H), 4.15-4.12 (m, 1H), 6-methylthieno[2,3-b]pyridine-2- 3.79-3.75 (m, 1H), 3.55-3.22 (m, 7H), carboxamide 3.15-3.13 (m, 1H), 2.82-2.68 (m, 4H), 2.59 (s, 3H), 2.33 (s, 3H), 2.01-1.90 (m, 1H), 1.87-1.82 (m, 1H). 312 3-amino-N-[(6S)-2-[(3S,4S)-3- 481 (CDCl3, 400 MHz) δ (ppm): 7.18 (d, J = +++ + methoxy-4- 8.4 Hz, 1H), 6.90 (s, 1H), 6.36 (br s, (methylamino)pyrrolidin-1-yl]- 2H), 6.23 (d, J = 8.4 Hz, 1H), 5.48 (d, J = 5,6,7,8-tetrahydroquinolin-6-yl]- 7.2 Hz, 1H), 4.44-4.39 (m, 1H), 3.88- 4,6-dimethylthieno[2,3- 3.74 (m, 3H), 3.51-3.45 (m, 1H), 3.44 (s, b]pyridine-2-carboxamide 3H), 3.37-3.30 (m, 2H), 3.12-3.07 (m, 1H), 2.98-2.93 (m, 2H), 2.77 (s, 3H), 2.70-2.63 (m, 1H), 2.61 (s, 3H), 2.55 (s, 3H), 2.25-2.23 (m, 1H), 1.94-1.90 (m, 1H). 313 3-amino-N-[(3R)-7-[(3R,4R)-3- 482 (DMSO-d6, 400 MHz) δ (ppm): 8.32 (d, ++++ ++ amino-4- J = 8.4 Hz, 1H), 7.48 (br s, 1H), 7.31 (d, (ethoxymethyl)pyrrolidin-1-yl]- J = 8.4 Hz, 1H), 7.21 (br s, 2H), 6.86 (d, 3,4-dihydro-2H-1-benzopyran-3- J = 8.4 Hz, 1H), 6.08 (d, J = 8.4 Hz, 1H), yl]-6-methylthieno[2,3- 5.88 (s, 1H), 4.30-4.26 (m, 1H), 4.15- b]pyridine-2-carboxamide 4.13 (m, 1H), 3.81-3.76 (m, 1H), 3.64- 3.55 (m, 1H), 3.52-3.50 (m, 1H), 3.46- 3.35 (m, 4H), 3.25-3.21 (m, 1H), 3.09- 3.05 (m, 1H), 2.96-2.93 (m, 1H), 2.89- 2.77 (m, 2H), 2.59 (s, 3H), 2.45-2.38 (m, 1H), 1.60 (br s, 2H), 1.15-1.11 (m, 3H). 314 3-amino-N-[(3R)-7-[(3S,4S)-3- 482 (DMSO-d6, 400 MHz) δ (ppm): 8.32 (d, ++++ +++ amino-4- J = 8.4 Hz, 1H), 7.48 (br s, 1H), 7.31 (d, (ethoxymethyl)pyrrolidin-1-yl]- J = 8.4 Hz, 1H), 7.21 (br s, 2H), 6.86 (d, 3,4-dihydro-2H-1-benzopyran-3- J = 8.4 Hz, 1H), 6.08 (d, J = 8.8 Hz, 1H), yl]-6-methylthieno[2,3- 5.88 (s, 1H), 4.30-4.26 (m, 1H), 4.15- b]pyridine-2-carboxamide 4.13 (m, 1H), 3.82-3.77 (m, 1H), 3.64- 3.55 (m, 2H), 3.47-3.35 (m, 4H), 3.25- 3.21 (m, 1H), 3.09-3.05 (m, 1H), 2.96- 2.94 (m, 1H), 2.89-2.79 (m, 2H), 2.59 (s, 3H), 2.44-2.39 (m, 1H), 1.79 (br s, 2H), 1.15-1.11 (m, 3H). 315 3-amino-N-[(6S)-2-[(3S,4S)-3- 467 (CDCl3, 400 MHz) δ (ppm): 7.82 (d, J = +++ ++ amino-4-methoxypiperidin-1-yl]- 8.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 2H), 5,6,7,8-tetrahydroquinolin-6-yl]- 6.53 (d, J = 8.8 Hz, 1H), 6.05 (br s, 2H), 6-methylthieno[2,3-b]pyridine-2- 5.52 (d, J = 7.6 Hz, 1H), 4.46-4.42 (m, carboxamide 1H), 4.31-4.23 (m, 2H), 3.49 (s, 3H), 3.13-3.08 (m, 2H), 2.98-2.89 (m, 4H), 2.77-2.61 (m, 5H), 2.26-2.14 (m, 2H), 1.97-1.85 (m, 1H), 1.84 (br s, 2H), 1.55- 146 (m, 1H). 316 3-amino-N-[(6S)-2-[(3R,4R)-3- 467 (CDCl3, 400 MHz) δ (ppm): 7.82 (d, J = +++ + amino-4-methoxypiperidin-1-yl]- 8.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 2H), 5,6,7,8-tetrahydroquinolin-6-yl]- 6.53 (d, J = 8.4 Hz, 1H), 6.06 (br s, 2H), 6-methylthieno[2,3-b]pyridine-2- 5.52 (d, J = 7.6 Hz, 1H), 4.46-4.41 (m, carboxamide 1H), 4.31-4.23 (m, 2H), 3.45 (s, 3H), 3.13-3.04 (m, 2H), 2.99-2.89 (m, 4H), 2.74-2.64 (m, 5H), 2.23-2.15 (m, 2H), 1.98-1.89 (m, 1H), 1.69 (br s, 2H), 1.54- 1.46 (m, 1H). 317 3-amino-N-[(3R)-7-[(3S,4S)-3- 482 (CDCl3, 400 MHz) δ (ppm): 6.95 (d, J = ++++ ++ amino-4-methoxypiperidin-1-yl]- 8.4 Hz, 1H), 6.88 (s, 1H), 6.56 (d, J = 3,4-dihydro-2H-1-benzopyran-3- 8.4 Hz, 1H), 6.45 (s, 1H), 6.34 (br s, yl]-4,6-dimethylthieno[2,3- 2H), 5.69 (d, J = 7.6 Hz, 1H), 4.62-4.58 b]pyridine-2-carboxamide (m, 1H), 4.23-4.15 (m, 2H), 3.67-3.60 (m, 2H), 3.44 (s, 3H), 3.15-3.09 (m, 1H), 3.03-2.91 (m, 2H), 2.83-2.78 (m, 2H), 2.76 (s, 3H), 2.63-2.43 (m, 4H), 2.18- 2.14 (m, 1H). 318 3-amino-N-[(3R)-7-[(3R,4R)-3- 482 (CDCl3, 400 MHz) δ (ppm): 6.95 (d, J = ++++ ++ amino-4-methoxypiperidin-1-yl]- 8.4 Hz, 1H), 6.88 (s, 1H), 6.56 (d, J = 3,4-dihydro-2H-1-benzopyran-3- 8.4 Hz, 1H), 6.45 (s, 1H), 6.34 (br s, yl]-4,6-dimethylthieno[2,3- 2H), 5.71-5.69 (m, 1H), 4.62-4.58 (m, b]pyridine-2-carboxamide 1H), 4.23-4.15 (m, 2H), 3.68-3.59 (m, 2H), 3.44 (s, 3H), 3.15-3.09 (m, 1H) 3.03-2.96 (m, 2H), 2.83-2.78 (m, 2H), 2.75 (s, 3H), 2.65-2.61 (m, 1H), 2.59 (s, 3H), 2.18-2.14 (m, 1H), 1.61-1.58 (m, 1H). 319 7-amino-N-[(2S)-6-[(3S,4S)-3- 481 (DMSO-d6, 400 MHz) δ (ppm): 8.65 (s, +++ + amino-4-(propan-2- 1H), 7.78 (br s, 1H), 6.91 (br s, 2H), yloxy)pyrrolidin-1-yl]-1,2,3,4- 6.87 (d, J = 8.4 Hz, 1H), 6.31 (d, J = 8.4 tetrahydronaphthalen-2-yl]-3- Hz, 1H), 6.22 (s, 1H), 4.13-4.09 (m, 1H), methylthieno[2,3-b]pyrazine-6- 3.81-3.80 (m, 1H), 3.77-3.70 (m, 1H), carboxamide 3.56-3.52 (m, 1H), 3.40-3.32 (m, 2H), 3.03-3.01 (m, 1H), 2.90-2.69 (m, 5H), 2.65 (s, 3H), 2.04-1.73 (m, 4H), 1.13- 1.11 (m, 6H). 320 3-amino-N-[(6S)-2-(3S,4S)-3- 481 (DMSO-d6, 400 MHz) δ (ppm): 8.31 (d, +++ + amino-4-(propan-2- J = 8.4 Hz, 1H), 7.56 (br s, 1H), 7.31 (d, yloxy)pyrrolidin-1-yl]-5,6,7,8- J = 8.0 Hz, 1H), 7.19-7.15(m, 3H), 6.22 tetrahydroquinolin-6-yl]-6- (d, J = 8.4 Hz, 1H), 4.16-4.11 (m, 1H), methylthieno[2,3-b]pyridine-2- 3.79-3.63 (m, 3H), 3.51-3.47 (m, 1H), carboxamide 3.34-3.32 (m, 1H), 3.22-3.19 (m, 1H), 3.11-3.08 (m, 1H), 2.82-2.68 (m, 4H), 2.59 (s, 3H), 2.01-1.99 (m, 1H), 1.90- 1.75 (m, 3H), 1.13-1.07 (m, 6H). 321 3-amino-N-[(6S)-2-[(3S,4R)-3- 481 (DMSO-d6, 400 MHz) δ (ppm): 8.31 (d, ++ + amino-4-(propan-2- J = 8.0 Hz, 1H), 7.56 (br s, 1H), 7.31 (d, yloxy)pyrrolidin-1-yl]-5,6,7,8- J = 8.0 Hz, 1H), 7.19-7.15 (m, 3H), 6.20 tetrahydroquinolin-6-yl]-6- (d, J = 8.4 Hz, 1H), 4.13-4.12 (m, 1H), methylthieno[2,3-b]pyridine-2- 3.95-3.92 (m, 1H), 3.75-3.70 (m, 1H), carboxamide 3.50-3.42 (m, 3H), 3.36-3.30 (m, 1H), 3.01-2.98 (m, 1H), 2.78-2.68 (m, 4 H), 2.59 (s, 3H), 2.01-1.98 (m, 1H), 1.88- 1.80 (m, 1 H), 1.65 (br s, 2H), 1.16-1.11 (m, 6 H). 322 3-amino-N-[(6S)-2-[(3R,4S)-3- 481 (DMSO-d6 400 MHz) δ (ppm): 8.31 (d, ++ + amino-4-(propan-2- J = 8.0 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), yloxy)pyrrolidin-1-yl]-5,6,7,8- 7.31 (d, J = 8.0 Hz, 1H), 7.19-7.15 (m, tetrahydroquinolin-6-yl]-6- 3H), 6.20 (d, J = 8.4 Hz, 1H), 4.12 (br s, methylthieno[2,3-b]pyridine-2- 1H), 3.94-3.93 (m, 1H), 3.76-3.70 (m, carboxamide 1H), 3.50-3.42 (m, 3H), 3.37-3.30 (m, 1H), 3.00-2.96 (m, 1H), 2.82-2.68 (m, 4H), 2.59 (s, 3H), 2.01-1.98 (m, 1H), 1.89-1.84 (m, 1 H), 1.65 (br s, 2H), 1.18- 1.12 (m, 6 H). 323 3-amino-N-[(3R)-7-[(3S,4R)-3- 482 (DMSO-d6, 400 MHz) δ (ppm): 7.52 (br ++++ +++ amino-4-ethoxypyrrolidin-1-yl]- s, 1H), 7.05 (s, 1H), 6.88-6.82 (m, 3H), 3,4-dihydro-2H-1-benzopyran-3- 6.09-6.06 (m, 1H), 5.89 (s, 1H), 4.30- yl]-4,6-dimethylthieno[2,3- 4.27 (m, 1H), 4.15-4.12 (m, 1H), 3.86- b]pyridine-2-carboxamide 3.76 (m, 2H), 3.60-3.47 (m, 3H), 3.36- 3.30 (m, 5H), 3.23-3.19 (m, 1H), 2.89- 2.79 (m, 3H), 2.73 (s, 3H), 1.82 (br s, 2H), 1.17-1.13 (m, 3 H). 324 3-amino-N-[(3R)-7-[(3R,4S)-3- 482 (DMSO-d6 400 MHz) δ (ppm): 7.51 (br +++ ++ amino-4-ethoxypyrrolidin-1-yl]- s, 1H), 7.05 (s, 1H), 6.88-6.82 (m, 3H), 3,4-dihydro-2H-1-benzopyran-3- 6.08-6.06 (m, 1H), 5.89 (s, 1H), 4.30- yl]-4,6-dimethylthieno[2,3- 4.26 (m, 1H), 4.15-4.12 (m, 1H), 3.85- b]pyridine-2-carboxamide 3.77 (m, 2H), 3.62-3.45 (m, 3H), 3.36- 3.32 (m, 5H), 3.23-3.19 (m, 1H), 2.89- 2.78 (m, 3H), 2.73 (s, 3H), 162 (br s, 2H), 1.17-1.13 (m, 3 H). 325 3-amino-N-[(3R)-7-[(3S,4S)-4- 469 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, +++ + amino-3-methoxy-3- J = 8.4 Hz, 1H), 7.54 (d, J = 7.2 Hz, 1H), methylpyrrolidin-1-yl]-2H,3H,4H- 7.32 (d, J = 8.4 Hz, 1H), 7.25-7.20 (m, pyrano[2,3-b]pyridin-3-yl]-6- 3H), 5.99 (d, J = 8.0 Hz, 1H), 4.27-4.22 methylthieno[2,3-b]pyridine-2- (m, 1H), 4.21-4.19 (m, 1H), 3.94 (t, J = carboxamide 10 Hz, 1H), 3.55-3.51 (m, 1H), 3.44-3.41 (m, 1H), 3.31-3.25 (m, 2H), 3.16 (s, 3H), 3.04-3.01 (m, 1H), 2.87-2.80 (m, 2H), 2.59 (s, 3H), 1.66 (br s, 2H), 1.23 (s, 3H). 326 3-amino-N-[(3R)-7-[(3R,4R)-4- 469 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, +++ + amino-3-methoxy-3- J = 8.4 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), methylpyrrolidin-1-yl]-2H,3H,4H- 7.32 (d, J = 8.4 Hz, 1H), 7.25-7.22 (m, pyrano[2,3-b]pyridin-3-yl]-6- 3H), 5.99 (d, J = 8.4 Hz, 1H), 4.27-4.22 methylthieno[2,3-b]pyridine-2- (m, 1H), 4.21-4.19 (m, 1H), 3.94 (t, J = carboxamide 10 Hz, 1H), 3.55-3.51 (m, 1H), 3.44-3.41 (m, 1H), 3.31-3.25 (m, 2H), 3.16 (s, 3H), 3.04-3.01 (m, 1H), 2.87-2.80 (m, 2H), 2.59 (s, 3H), 1.66 (br s, 2H), 1.23 (s, 3H). 327 3-amino-N-[(6S)-2-[(3R,4S)-3- 467 (DMSO-d6 400 MHz) δ (ppm): 8.28 (d, +++ ++ amino-4- J = 8.0 Hz, 1H), 7.56 (br s, 1H), 7.31 (d, (methoxymethyl)pyrrolidin-1-yl]- J = 8.4 Hz, 1H), 7.19-7.16 (m, 3H), 6.21 5,6,7,8-tetrahydroquinolin-6-yl]- (d, J = 8.4 Hz, 1H), 4.16-4.10 (m, 1H), 6-methylthieno[2,3-b]pyridine-2- 3.63-3.55 (m, 2H), 3.52-3.48 (m, 1H), carboxamide 3.32 (s, 3H), 3.27-3.17 (m, 1H), 3.15- 3.08 (m, 1H), 2.99-2.95 (m, 1H), 2.80- 2.67 (m, 5H), 2.58 (s, 3H), 2.17-2.12 (m, 1H), 2.00-1.98 (m, 1H), 1.87-1.82 (m, 1H). 328 3-amino-N-[(6S)-2-[(3S,4R)-3- 467 (DMSO-d6, 400 MHz) δ (ppm): 8.30 (d, ++ + amino-4- J = 8.4 Hz, 1H), 7.55 (br s, 1H), 7.31 (d, (methoxymethyl)pyrrolidin-1-yl]- J = 8.4 Hz, 1H), 7.19-7.15 (m, 3H), 6.21 5,6,7,8-tetrahydroquinolin-6-yl]- (d, J = 8.4 Hz, 1H), 4.13-4.10 (m, 1H), 6-methylthieno[2,3-b]pyridine-2- 3.64-3.57 (m, 2H), 3.51-3.45 (m, 1H), carboxamide 3.34-3.23 (m, 1H), 3.21 (s, 3H), 3.20- 3.12 (m, 1H), 3.10-3.08 (m, 1H), 2.99- 2.97 (m, 1H), 2.81-2.67 (m, 4H), 2.58 (s, 3H), 2.20-2.15 (m, 1H), 2.01-1.89 (m, 1H), 1.86-1.79 (m, 1H). 329 N-[(6S)-2-[(4aS,7aS)-4,4- 499 (DMSO-d6 400 MHz) δ (ppm): 8.31 (d , +++ ++ difluoro-octahydro-1H- J = 8.4 Hz, 1H), 7.57 (br s, 1H), 7.31 (d, pyrrolo[3,4-b]pyridin-6-yl]- J = 8.4 Hz, 1H), 7.22-7.16 (m, 3H), 6.25 5,6,7,8-tetrahydroquinolin-6-yl]- (d, J = 8.4 Hz, 1H), 4.17-4.13 (m, 1H), 3-amino-6-methylthieno[2,3- 3.58-3.33 (m, 5H), 2.98-2.94 (m, 1H), b]pyridine-2-carboxamide 2.82-2.65 (m, 6H), 2.59 (s, 3H), 2.08- 1.85 (m, 4 H). 330 N-[(6S)-2-[(4aR,7aR)-4,4- 499 (DMSO-d6, 400 MHz) δ (ppm): 8.31 (d, +++ + difluoro-octahydro-1H- J = 8.4 Hz, 1H), 7.57 (br s, 1H), 7.31 (d, pyrrolo[3,4-b]pyridin-6-yl]- J = 8.4 Hz, 1H), 7.22-7.16 (m, 2H), 6.25 5,6,7,8-tetrahydroquinolin-6-yl]- (d, J = 8.4 Hz, 1H), 4.17-4.13 (m, 1H), 3-amino-6-methylthieno[2,3- 3.58-3.33 (m, 5H), 2.98-2.94 (m, 1H), b]pyridine-2-carboxamide 2.82-2.65 (m, 6H), 2.59 (s, 3H), 2.08- 1.85 (m, 4 H). 331 3-amino-N-[(6S)-2-[(3R,4S)-3- 467 (DMSO-d6, 400 MHz) δ (ppm): 8.31 (d, +++ + hydroxy-3-methyl-4- J = 8.4 Hz, 1H), 7.56 (br s, 1H), 7.31 (d, (methylamino)pyrrolidin-1-yl]- J = 8.4 Hz, 1H), 7.18-7.16 (m, 3H), 6.18 5,6,7,8-tetrahydroquinolin-6-yl]- (d, J = 8.4 Hz, 1H), 4.82-4.78 (m, 1H), 6-methylthieno[2,3-b]pyridine-2- 4.14-4.11 (m, 1H), 3.60-3.53 (m, 1H), carboxamide 3.29-3.24 (m, 2H), 3.17-3.13 (m, 1H), 2.90-2.87 (m, 1H), 2.81-2.68 (m, 4H), 2.59 (s, 3H), 2.33 (s, 3H), 2.01-1.97 (m, 1H), 1.90-1.81 (m, 1H), 1.68 (br s, 1H), 1.21 (s, 3H). 332 3-amino-N-[(6S)-2-[(3S,4R)-3- 467 (DMSO-d6, 400 MHz) δ (ppm): 8.31 (d, +++ + hydroxy-3-methyl-4- J = 8.4 Hz, 1H), 7.56 (br s, 1H), 7.31 (d, (methylamino)pyrrolidin-1-yl]- J = 8.4 Hz, 1H), 7.18-7.16 (m, 3H), 6.18 5,6,7,8-tetrahydroquinolin-6-yl]- (d, J = 8.8 Hz, 1H), 4.82-4.78 (m, 1H), 6-methylthieno[2,3-b]pyridine-2- 4.13-4.12 (m, 1H), 3.61-3.57 (m, 1H), carboxamide 3.30-3.23 (m, 2H), 3.15-3.12 (m, 1H), 2.90-2.87 (m, 1H), 2.81-2.67 (m, 4H), 2.59 (s, 3H), 2.34 (s, 3H), 2.01-1.98 (m, 1H), 1.89-1.81 (m, 1H), 1.70 (br s, 1H), 1.21 (s, 3H). 333 3-amino-N-[(3R)-7-](2S,3S,4S)- 468 (DMSO-d6 400 MHz) δ (ppm): 8.33 (d, ++++ +++ 3-amino-4-methoxy-2- J = 8.4 Hz, 1H), 7.48 (br s, 1H), 7.31 (d, methylpyrrolidin-1-yl]-3,4- J = 8.4 Hz, 1H), 7.21 (br s, 2H), 6.87 (d, dihydro-2H-1-benzopyran-3-yl]- J = 8.4 Hz, 1H), 6.13 (d, J = 8.4 Hz, 1H), 6-methylthieno[2,3-b]pyridine-2- 5.93 (s, 1H), 4.33-4.24 (m, 1H), 4.16- carboxamide 4.13 (m, 1H), 3.82-3.77 (m, 1H), 3.59- 3.57 (m, 1H), 3.47-3.28 (m, 5H), 3.17- 3.16 (m, 1H), 2.89-2.78 (m, 2H), 2.59 (s, 3H), 2.08 (br s, 2H), 1.20-1.18 (m, 3H). 334 3-amino-N-[(3R)-7-[(2S,3S,4R)- 468 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, ++++ ++++ 4-amino-3-methoxy-2- J = 8.4 Hz, 1H), 7.49 (br s, 1H), 7.31 (d, methylpyrrolidin-1-yl]-3,4- J = 8.4 Hz, 1H), 7.21 (s, 2H), 6.87 (d, J = dihydro-2H-1-benzopyran-3-yl]- 8.8 Hz, 1H), 6.12 (d, J = 6.8 Hz, 1H), 6-methylthieno[2,3-b]pyridine-2- 5.93 (s, 1H), 4.30-4.26 (m, 1H), 4.15- carboxamide 4.13 (m, 1H), 4.04-3.97 (m, 1H), 3.82- 3.77 (m, 1H), 3.46-3.30 (m, 6H), 2.90- 2.68(m, 3H), 2.59 (s, 3H), 1.79 (br s, 2H), 0.99-0.96(m, 3H). 335 3-amino-N-[(3R)-7-[(2R,3R,4R)- 468 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, ++++ ++ 3-amino-4-methoxy-2- J = 8.0 Hz, 1H), 7.50 (br s, 1H), 7.32 (d, methylpyrrolidin-1-yl]-3,4- J = 8.0 Hz, 1H), 7.21 (s, 2H), 6.87 (d, J = dihydro-2H-1-benzopyran-3-yl]- 8.4 Hz, 1H), 6.12 (d, J = 7.6 Hz, 1H), 6-methylthieno[2,3-b]pyridine-2- 5.93 (s, 1H), 4.30-4.26 (m, 1H), 4.15- carboxamide 4.13 (m, 1H), 3.82-3.77 (m, 1H), 3.58- 3.56 (m, 1H), 3.47-3.31 (m, 6H), 3.17- 3.15 (m, 1H), 2.90-2.77 (m, 2H), 2.59 (s, 3H), 1.71 (brs, 2H), 1.18 (d, J = 6.4 Hz, 3H). 336 3-amino-N-[(3R)-7-[(2R,3R,4S)- 468 (DMSO-d6 400 MHz) δ (ppm): 8.32 (d, ++++ ++ 4-amino-3-methoxy-2- J = 8.0 Hz, 1H), 7.50 (br s, 1H), 7.31 (d, methylpyrrolidin-1-yl]-3,4- J = 8.4 Hz, 1H), 7.22 (s, 2H), 6.87 (d, J = dihydro-2H-1-benzopyran-3-yl]- 8.4 Hz, 1H), 6.15-6.12 (m, 1H), 5.92 6-methylthieno[2,3-b]pyridine-2- (s, 1H), 4.30-4.26 (m, 1H), 4.15-4.12 (m, carboxamide 1H), 4.04-4.00 (m, 1H), 3.81-3.76 (m, 1H), 3.42-3.35 (m, 6H), 2.85-2.72 (m, 3H), 2.59 (s, 3H), 0.99-0.96 (m, 3H). 337 3-amino-N-[(3R)-7-[(8R)-8- 466 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, ++++ ++ amino-5-oxa-2- J = 8.4 Hz, 1H), 7.52 (d, J = 7.2 Hz, 1H), azaspiro[3.4]octan-2-yl]-3,4- 7.32 (d, J = 8.0 Hz, 1H), 7.22 (s, 2H), dihydro-2H-1-benzopyran-3-yl]- 6.89 (d, J = 8.0 Hz, 1H), 6.03 (d, J = 8.0 6-methylthieno[2,3-b]pyridine-2- Hz, 1H), 5.86 (s, 1H), 4.30-4.26 (m, 1H), carboxamide 4.16-4.09 (m, 2H), 3.87-3.69 (m, 4H), 3.53-3.48 (m, 2H), 3.32-3.30 (m, 1H), 2.90-2.79 (m, 2H), 2.58 (s, 3H), 2.10- 2.01 (m, 1H), 1.89-1.80 (m, 2H), 1.66- 1.60 (m, 1H). 338 3-amino-N-[(3R)-7-[(8S)-8- 466 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, +++ ++ amino-5-oxa-2- J = 8.4 Hz, 1H), 7.52 (d, J = 7.2 Hz, 1H), azaspiro[3.4]octan-2-yl]-3,4- 7.32 (d, J = 8.0 Hz, 1H), 7.22 (s, 2H), dihydro-2H-1-benzopyran-3-yl]- 6.89 (d, J = 8.0 Hz, 1H), 6.03 (d, J = 8.0 6-methylthieno[2,3-b]pyridine-2- Hz, 1H), 5.86 (s, 1H), 4.30-4.26 (m, 1H), carboxamide 4.16-4.09 (m, 2H), 3.87-3.69 (m, 4H), 3.53-3.48 (m, 2H), 3.32-3.30 (m, 1H), 2.90-2.79 (m, 2H), 2.58 (s, 3H), 2.10- 2.01 (m, 1H), 1.89-1.80 (m, 2H), 1.66- 160 (m, 1H). 339 3-amino-N-[(3R)-7-[(4R,8R)-8- 466 (DMSO-d6 400 MHz) δ (ppm): 8.33 (d, ++++ ++ amino-1-oxa-6- J = 8.4 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), azaspiro[3.4]octan-6-yl]-3,4- 7.32 (d, J = 8.4 Hz, 1H), 7.23 (s, 2H), dihydro-2H-1-benzopyran-3-yl]- 6.87 (d, J = 8.4 Hz, 1H), 6.07 (d, J = 8.4 6-methylthieno[2,3-b]pyridine-2- Hz, 1H), 5.87 (s, 1H), 4.44-4.34 (m, 2H), carboxamide 4.29-4.25 (m, 1H), 4.15-4.12 (m, 1H), 3.80-3.75 (m, 1H), 3.59-3.56 (m, 1H), 3.40-3.38 (m, 1H), 3.23-3.20 (m, 1H), 2.89-2.81 (m, 2H), 2.79-2.67 (m, 2 H) 2.63-2.56 (m, 5H), 1.95 (brs, 2H). 340 3-amino-N-[(3R)-7-[(4S,8S)-8- 466 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, ++++ ++ amino-1-oxa-6- J = 8.4 Hz, 1H), 7.51 (br s, 1H), 7.32 (d, azaspiro[3.4]octan-6-yl]-3,4- J = 8.0 Hz, 1H), 7.22 (s, 2H), 6.87 (d, J = dihydro-2H-1-benzopyran-3-yl]- 7.6 Hz, 1H), 6.07 (d, J = 8.4 Hz, 1H), 6-methylthieno[2,3-b]pyridine-2- 5.87 (s, 1H), 4.42-4.36 (m, 2H), 4.27- carboxamide 4.25 (m, 1H), 4.15-4.12 (m, 1H), 3.81- 3.76 (m, 1H), 3.59-3.57 (m, 1H), 3.40- 3.38 (m, 1H), 3.24-3.20 (m, 1H), 2.89- 2.81 (m, 2 H), 2.74-2.67 (m, 2 H), 2.63- 2.56 (m, 5H), 2.12 (br s, 2H). 341 3-amino-N-[(6S)-2-[(3S,4R)-4- 481 (MeOH-d4, 400 MHz) δ (ppm): 8.22 (d, J = +++ ++ amino-3-(methoxymethyl)-3- 8.4 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), methylpyrrolidin-1-yl]-5,6,7,8- 7.28 (d, J = 8.8 Hz, 1H), 6.32 (d, J = 8.4 tetrahydroquinolin-6-yl]-6- Hz, 1H), 4.28-4.25 (m, 1H), 3.88-3.84 methylthieno[2,3-b]pyridine-2- (m, 1H) 3.64-3.60 (m, 1H), 3.42-3.37 carboxamide (m, 6H), 3.36-3.33 (m, 2H), 2.98-2.90 (m, 3H), 2.79-2.73 (m, 1H), 2.66 (s, 3H), 2.19-2.16 (m, 1H), 1.97-1.91 (m, 1H), 1.15 (s, 3H). 342 3-amino-N-[(6S)-2-[(3R,4R)-4- 481 (DMSO-d6, 400 MHz) δ (ppm): 8.31 (d, J = +++ ++ amino-3-(methoxymethyl)-3- 8.4 Hz, 1H), 7.57 (d, J = 8..0 Hz, 1H), methylpyrrolidin-1-yl]-5,6,7,8- 7.31 (d, J = 8.4 Hz, 1H), 7.19-7.16 (m, tetrahydroquinolin-6-yl]-6- 3H), 6.19 (d, J = 8.4 Hz, 1H), 4.28-4.23 methylthieno[2,3-b]pyridine-2- (m, 1H), 3.65-3.57 (m, 1H), 3.46-3.43 carboxamide (m, 1H), 3.32-3.27 (m, 5H), 3.20-3.15 (m, 2H), 3.04-3.01 (m, 1H), 2.77-2.71 (m, 4H), 2.59 (s, 3H), 2.09-1.98 (m, 2H), 1.95-1.79 (m, 2H), 1.04 (s, 3H). 343 3-amino-N-[(6S)-2-[(3S,4S)-4- 481 (DMSO-d6, 400 MHz) δ (ppm): 8.30 (d, J = +++ ++ amino-3-(methoxymethyl)-3- 8.4 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), methylpyrrolidin-1-yl]-5,6,7,8- 7.31 (d, J = 8.4 Hz, 1H), 7.18-7.14 (m, tetrahydroquinolin-6-yl]-6- 3H), 6.18 (d, J = 8.4 Hz, 1H), 4.13-4.06 methylthieno[2,3-b]pyridine-2- (m, 1H), 3.62-3.58 (m, 1H), 3.47-3.45 carboxamide (m, 1H), 3.36-3.27 (m, 5H), 3.18-3.14 (m, 1H), 3.10-3.06 (m, 1H), 3.02-2.99 (m, 1H), 2.81-2.71 (m, 5H), 2.51 (s, 3H), 2.05-1.98 (m, 1H), 1.88-1.82 (m, 1H), 1.70-1.68 (m, 1H), 1.04 (s, 3H). 344 3-amino-N-[(6S)-2-1(3R,4S)-4- 481 (DMSO-d6 400 MHz) δ (ppm): 8.29 (d, J = +++ ++ amino-3-(methoxymethyl)-3- 8.4 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), methylpyrrolidin-1-yl]-5,6,7,8- 7.31 (d, J = 8.0 Hz, 1H), 7.18-7.14 (m, tetrahydroquinolin-6-yl]-6- 3H), 6.18 (d, J = 8.4 Hz, 1H), 4.14-4.12 methylthieno[2,3-b]pyridine-2- (m, 1H), 3.62-3.58 (m, 1H), 3.33-3.27 carboxamide (m, 4H), 3.25-3.22 (m, 4H), 3.02-2.97 (m, 1H), 2.81-2.67 (m, 4H), 2.59 (s, 3H), 2.01-1.98 (m, 1H), 1.88-1.76 (m, 3H), 0.93 (s, 3H). 345 3-amino-N-[(6S)-2-[(3R,4R)-3- 473 (DMSO-d6 400 MHz) δ (ppm): 8.30 (d, +++ ++ amino-4- J = 8.4 Hz, 1H), 7.56 (br s, 1H), 7.31 (d, (difluoromethyl)pyrrolidin-1-yl]- J = 8.4 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 5,6,7,8-tetrahydroquinolin-6-yl]- 7.15 (br s, 2H), 6.26 (d, J = 8.4 Hz,, 2H), 6-methylthieno[2,3-b]pyridine-2- 4.14-4.11 (m, 1H), 3.68-3.64 (m, 1H), carboxamide 3.54-3.45 (m, 3H), 3.29-3.23 (m, 1H), 2.83-2.67 (m, 5H), 2.58 (s, 3H), 2.02- 1.90 (m, 2H), 1.87-1.82 (m, 1H). 346 3-amino-N-[(6S)-2-[(3S,4S)-3- 473 (DMSO-d6, 400 MHz) δ (ppm): 8.30 (d, +++ ++ amino-4- J = 8.8 Hz, 1H), 7.56 (br s, 1H), 7.31 (d, (difluoromethyl)pyrrolidin-1-yl]- J = 8.4 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 5,6,7,8-tetrahydroquinolin-6-yl]- 7.15 (s, 2H), 6.26 (d, J = 7.6 Hz, 2H), 6-methylthieno[2,3-b]pyridine-2- 4.15-4.12 (m, 1H), 3.67-3.64 (m, 1H), carboxamide 3.54-3.48 (m, 3H), 3.29-3.23 (m, 1H), 2.81-2.67 (m, 5H), 2.58 (s, 3H), 1.98- 1.90 (m, 1H), 1.87-1.82 (m, 2H). 347 3-amino-N-[(6S)-2-[(3R,4S)-3- 473 (DMSO-d6, 400 MHz) δ (ppm): 8.31 (d, +++ ++ amino-4- J = 8.4 Hz, 1H), 7.57 (br s, 1H), 7.31 (d, (difluoromethyl)pyrrolidin-1-yl]- J = 8.4 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 5,6,7,8-tetrahydroquinolin-6-yl]- 7.16 (br s, 2H), 6.34-6.05 (m, 2H), 4.16- 6-methylthieno[2,3-b]pyridine-2- 4.12 (m, 1H), 3.67-3.30 (m, 4H), 3.05- carboxamide 3.01 (m, 1H), 2.83-2.73 (m, 4H), 2.59 (s, 3H), 2.50-2.43 (m, 1H), 2.02-1.81 (m, 4H). 348 3-amino-N-[(3R)-7-[(3R,4R)-3- 483 (DMSO-d6, 400 MHz) δ (ppm): 7.56 (d, +++ + amino-4- J = 6.8 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), (methoxymethyl)pyrrolidin-1-yl]- 7.05 (s, 1H), 6.86 (br s, 2H), 6.00 (d, J = 2H,3H,4H-pyrano[2,3-b]pyridin- 8.8 Hz, 1H), 4.28-4.26 (m, 1H), 4.21- 3-yl]-4,6-dimethylthieno[2,3- 4.18 (m, 1H), 3.94 (t, J = 10.0 Hz, 1H), b]pyridine-2-carboxamide 3.59-3.51 (m, 2H), 3.48-3.37 (m, 3H), 3.28 (s, 3H), 3.19-3.15 (m, 2H), 2.87- 2.81 (m, 2H), 2.73 (s, 3H), 2.51 (s, 3H), 2.45-2.39 (m, 1H), 1.69 (br s, 2H). 349 3-amino-N-[(3R)-7-[(3S,4S)-3- 483 (DMSO-d6, 400 MHz) δ (ppm): 7.56 (d, +++ ++ amino-4- J = 6.8 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), (methoxymethyl)pyrrolidin-1-yl]- 7.05 (s, 1H), 6.86 (br s, 2H), 6.00 (d, J = 2H,3H,4H-pyrano[2,3-b]pyridin- 8.0 Hz, 1H), 4.28-4.26 (m, 1H), 4.21- 3-yl]-4,6-dimethylthieno[2,3- 4.18 (m, 1H), 3.94 (t, J = 9.6 Hz, 1H), b]pyridine-2-carboxamide 3.59-3.51 (m, 2H), 3.48-3.37 (m, 3H), 3.28 (s, 3H), 3.19-3.15 (m, 2H), 2.87- 2.81 (m, 2H), 2.73 (s, 3H), 2.51 (s, 3H), 2.45-2.38 (m, 1H), 1.69 (br s, 2H). 350 3-amino-N-[(3R)-7-[(3S,4S)-3- 454 (DMSO-d6, 400 MHz) δ (ppm): 8.32 (d, +++ ++ hydroxy-4- J = 8.4 Hz, 1H), 7.49 (br s, 1H), 7.31 (d, (methylamino)pyrrolidin-1-yl]- J = 8.0 Hz, 1H), 7.22 (br s, 2H), 6.86 (d, 3,4-dihydro-2H-1-benzopyran-3- J = 8.4 Hz, 1H), 6.10-6.08 (m, 1H), 5.89 yl]-6-methylthieno[2,3- (s, 1H), 5.06-5.05 (m, 1H), 4.29-4.23 (m, b]pyridine-2-carboxamide 1H), 4.15-4.12 (m, 1H), 4.07-4.05 (m, 1H), 3.81-3.76 (m, 1H), 3.43-3.39 (m, 2H), 3.01-2.96 (m, 3H), 2.85-2.82 (m, 2H), 2.59 (s, 3H), 2.33 (s, 3H). 351 3-amino-N-[(3R)-7-[(7R)-7- 466 (DMSO-d6 400 MHz) δ (ppm): 8.33 (d, ++++ ++++ amino-2-oxa-5- J = 8.4 Hz, 1H), 7.53 (br s, 1H), 7.32 (d, azaspiro[3.4]octan-5-yl]-3,4- J = 8.4 Hz, 1H), 7.22 (br s, 2H), 6.96 (d, dihydro-2H-1-benzopyran-3-yl]- J = 8.4 Hz, 1H), 6.61-6.59 (m, 1H), 6.47 6-methylthieno[2,3-b]pyridine-2- (s, 1H), 5.16-5.12 (m, 2H), 4.65-4.63 (m, carboxamide 1H), 4.56-4.54 (m, 1H), 4.33-4.28 (m, 1H), 4.17-4.15 (m, 1H), 3.85-3.80 (m, 1H), 3.42-3.38 (m, 2H), 2.93-2.81 (m, 3H), 2.59 (s, 3H), 2.35-2.30 (m, 1H), 2.20-2.16 (m, 1H), 1.69 (br s, 2H). 352 3-amino-N-[(3R)-7-[(7S)-7- 466 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, ++++ +++ amino-2-oxa-5- J = 8.0 Hz, 1H), 7.53 (br s, 1H), 7.32 (d, azaspiro[3.4]octan-5-yl]-3,4- J = 8.4 Hz, 1H), 7.22 (br s, 2H), 6.96 (d, dihydro-2H-1-benzopyran-3-yl]- J = 8.4 Hz, 1H), 6.60 (d, J = 8.4 Hz, 1H), 6-methylthieno[2,3-b]pyridine-2- 6.48 (s, 1H), 5.15-5.13 (m, 2H), 4.65- carboxamide 4.63 (m, 1H), 4.56-4.54 (m, 1H), 4.35- 4.29 (m, 1H), 4.18-4.16 (m, 1H), 3.84- 3.82 (m, 1H), 3.40-3.37 (m, 2H), 2.93- 2.83 (m, 3H), 2.59 (s, 3H), 2.34-2.30 (m, 1H), 2.21-2.17 (m, 1H), 1.75 (br s, 2H). 353 N-[(6S)-2-[(3S,4S)-3-amino-4- 435 (DMSO-d6, 400 MHz) δ (ppm): 8.76 (s, ++ + methoxypyrrolidin-1-yl]-5,6,7,8- 1H), 8.47-8.44 (m, 2H), 7.68 (d, J = 3.6 tetrahydroquinolin-6-yl]-1-ethyl- Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 6.59 1H-pyrrolo[2,3-b]pyridine-5- (d, J = 3.6 Hz, 1H), 6.23 (d, J = 8.4 Hz, carboxamide 1H), 4.36-4.30 (m, 2 H), 4.17 (br s, 1H), 3.62-3.59 (m, 2H), 3.48-3.41 (m, 2H), 3.37-3.30 (m, 4H), 3.14-3.12 (m, 1H), 2.92-2.87 (m, 1H), 2.81-2.78 (m, 2H), 2.72-2.65 (m, 1H), 2.10-2.06 (m, 1H), 1.88-1.80(m, 2H), 1.41-1.38 (m, 3H). 354 3-amino-N-[(6S)-2-{3,8- 463 (DMSO-d6, 400 MHz) δ (ppm): 7.61 (br ++++ ++ diazabicyclo[3.2.1]octan-3-yl]- s, 1H), 7.21 (d, J = 8.8 Hz, 1H), 7.04 (s, 5,6,7,8-tetrahydroquinolin-6-yl]- 1H), 6.82 (br s, 2H), 6.45 (d, J = 8.8 Hz, 4,6-dimethylthieno[2,3- 1H), 4.17-4.13 (m, 1H), 3.77-3.73 (m, b]pyridine-2-carboxamide 2H), 3.48-3.47 (m, 2H), 2.82-2.68 (m, 10H), 2.49 (s, 3H), 2.00-1.80 (m, 2 H), 1.66-1.58 (m, 4 H). 355 5-chloro-N-[(3R)-7-{3,8- 503 (DMSO-d6, 400 MHz) δ (ppm): 9.14 (br +++ ++ diazabicyclo[3.2.1]octan-3-yl}- s, 1H), 8.39 (s, 1H), 8.36 (s, 1H), 6.38- 5,8-difluoro-3,4-dihydro-2H-1- 6.34 (m, 1H), 4.55-4.50 (m, 3H), 4.31- benzopyran-3-yl]-7-ethyl-7H- 4.26 (m, 1H), 4.20-4.15 (m, 1H), 3.42- pyrrolo[2,3-c]pyridazine-3- 3.40 (m, 2H), 3.08-3.04 (m, 2H), 3.02- carboxamide 2.99 (m, 2H), 2.82-2.80 (m, 2H), 1.81- 1.74 (m, 2H), 1.67-1.66 (m, 2H), 1.50- 1.47 (m, 3H). 356 5-chloro-N-[(3R)-8-cyano-7- 510 (DMSO-d6, 400 MHz) δ (ppm): 9.19 (br ++ ++ {3,8-diazabicyclo[3.2.1]octan-3- s, 1H), 8.40 (s, 1H), 8.36 (s, 1H), 6.50 yl}-5-fluoro-3,4-dihydro-2H-1- (d, J = 9.6 Hz, 1H), 4.55-4.50 (m, 3H), benzopyran-3-yl]-7-ethyl-7H- 4.41-4.38 (m, 1H), 4.31-4.27 (m, 1H), pyrrolo[2,3-c]pyridazine-3- 3.46-3.44 (m, 2H), 3.32-3.28 (m, 2H), carboxamide 2.98-2.89 (m, 4H), 1.90-1.89 (m, 2H), 1.65-1.63 (m, 2H), 1.51-1.47 (m, 3H). 357 3-amino-N-[(6S)-2-[(3S,4R)-3- 503 (DMSO-d6, 400 MHz) δ (ppm): 8.31 (d, +++ ++ amino-4-(1,1- J = 8.4 Hz, 1H), 7.59 (br s, 1H), 7.31 (d, difluoroethoxy)pyrrolidin-1-yl]- J = 8.0 Hz, 1H), 7.22-7.17 (m, 3H), 6.24 5,6,7,8-tetrahydroquinolin-6-yl]- (d, J = 8.4 Hz, 1H), 4.69-4.65 (m, 1H), 6-methylthieno[2,3-b]pyridine-2- 4.15-4.13 (m, 1H), 3.60-3.49 (m, 4H), carboxamide 3.00-2.94 (m, 1H), 2.78-2.68 (m, 4H), 2.59 (s, 3H), 2.02-1.95 (m, 1H), 1.85- 1.78 (m, 4H), 1.70 (br s, 2H). 358 3-amino-N-[(6S)-2-[(3R,4S)-3- 503 (DMSO-d6, 400 MHz) δ (ppm): 8.31 (d, ++ + amino-4-(1,1- J = 8.0 Hz, 1H), 7.59 (br s, 1H), 7.31 (d, difluoroethoxy)pyrrolidin-1-yl]- J = 8.4 Hz, 1H), 7.22-7.17 (m, 3H), 6.24 5,6,7,8-tetrahydroquinolin-6-yl]- (d, J = 8.4 Hz, 1H), 4.69-4.64 (m, 1H), 6-methylthieno[2,3-b]pyridine-2- 4.15-4.12 (m, 1H), 3.62-3.51 (m, 4H), carboxamide 3.00-2.94 (m, 1H), 2.82-2.68 (m, 4H), 2.59 (s, 3H), 2.01-1.98 (m, 1H), 1.87- 1.78 (m, 6H). 359 (6aS,7aR)-N-[(2S)-6-{3,8- 498 (DMSO-d6, 400 MHz) δ (ppm): 8.29 (s, + + diazabicyclo[3.2.1]octan-3-yl}-5- 1H), 8.18 (d, J = 7.2 Hz, 1H), 7.86 (s, (difluoromethyl)-8-fluoro- 1H), 7.49-7.22 (m, 1H), 7.05 (d, J = 10.8 1,2,3,4-tetrahydronaphthalen-2- Hz, 1H), 6.57 (s, 1H), 4.184.10 (br s, yl]-5H,6H,6aH,7H,7aH- 1H), 3.59-3.50(m, 5H), 3.24-3.16 (m, cyclopropa[c]1,8-naphthyridine- 1H), 3.07-2.86 (m, 4H), 2.67-2.58 (m, 2-carboxamide 3H), 2.08-1.93 (m, 2H), 1.88-1.86 (m, 2H), 1.80-1.68 (m, 4H), 0.96-0.90 (m, 2H) 360 (6aR,7aS)-N-[(2S)-6-{3,8- 498 (DMSO-d6, 400 MHz) δ (ppm): 8.29 (s, ++++ ++ diazabicyclo[3.2.1]octan-3-yl}-5- 1H), 8.18 (d, J = 7.2 Hz, 1H), 7.87 (s, (difluoromethyl)-8-fluoro- 1H), 7.50-7.22 (m, 1H), 7.05 (d, J = 10.8 1,2,3,4-tetrahydronaphthalen-2- Hz, 1H), 6.57 (s, 1H), 4.18-4.10 (br s, yl]-5H,6H,6aH,7H,7aH- 1H), 3.50-3.40 (m, 5H), 3.21-3.16 (m, cyclopropa[c]1,8-naphthyridine- 1H), 3.07-2.88 (m, 4H), 2.68-2.58 (m, 2-carboxamide 3H), 2.04-1.93 (m, 2H), 1.89-1.87 (m, 2H), 1.80-1.70 (m, 4H), 0.96-0.90 (m, 2H) 361 (6aS,7aR)-N-[(2R)-6-{3,8- 498 (DMSO-d6, 400 MHz) δ(ppm): 8.29 (s, + + diazabicyclo[3.2.1]octan-3-yl}-5- 1H), 8.18 (d, J = 6.8 Hz, 1H), 7.87 (s, (difluoromethyl)-8-fluoro- 1H), 7.50-7.22 (m, 1H), 7.05 (d, J = 11.2 1,2,3,4-tetrahydronaphthalen-2- Hz, 1H), 6.59 (s, 1H), 4.18-4.10 (br s, yl]-5H,6H,6aH,7H,7aH- 1H), 3.55-3.35 (m, 5H), 3.23-3.16 (m, cyclopropa[c]1,8-naphthyridine- 1H), 3.07-2.88 (m, 4H), 2.68-2.58 (m, 2-carboxamide 3H), 2.10-1.88 (m, 4H), 1.82-1.71 (m, 4H), 0.95-0.92 (m, 2H) 362 (6aR,7aS)-N-[(2R)-6-{3,8- 498 (DMSO-d6, 400 MHz) δ(ppm): 8.29 (m, ++ ++ diazabicyclo[3.2.1]octan-3-yl]-5- 1H), 8.19 (d, J = 6.8 Hz, 1H), 7.86 (s, (difluoromethyl)-8-fluoro- 1H), 7.49-7.22 (m, 1H), 7.05 (d, J = 11.2 1,2,3,4-tetrahydronaphthalen-2- Hz, 1H), 6.58 (s, 1H), 4.18-4.10 (br s, yl]-5H,6H,6aH,7H,7aH- 1H), 3.53-3.43 (m, 5H), 3.21-3.17 (m, cyclopropa[c]1,8-naphthyridine- 1H), 3.07-2.90 (m, 4H), 2.65-2.62 (m, 2-carboxamide 3H), 2.04-1.88 (m, 4H), 1.76-1.71 (m, 4H), 0.96-0.92 (m, 2H). 363 3-amino-N-[(6S)-2-[(3R,4S)-3- 491 (DMSO-d6, 400 MHz) δ(ppm): 8.29 (d, +++ ++ amino-4- J = 8.0 Hz, 1H), 7.57 (br s, 1H), 7.31 (d, (trifluoromethyl)pyrrolidin-1-yl]- J = 8.0 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 5,6,7,8-tetrahydroquinolin-6-yl]- 7.16 (br s, 2H), 6.31 (d, J = 8.4 Hz, 1H), 6-methylthieno[2,3-b]pyridine-2- 4.15-4.12 (m, 1H), 3.77-3.67 (m, 3H), carboxamide 3.49-3.45 (m, 1H), 3.11-3.05 (m, 1H), 2.96-2.92 (m, 1H), 2.83-2.68 (m, 4H), 2.59 (s, 3H), 2.17-1.80 (m, 4H). 364 3-amino-N-[(6S)-2-[(3S,4R)-3- 491 (DMSO-d6, 400 MHz) δ(ppm): 8.30 (d, +++ + amino-4- J = 8.4 Hz, 1H), 7.57 (br s, 1H), 7.31 (d, (trifluoromethyl)pyrrolidin-1-yl]- J = 8.4 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 5,6,7,8-tetrahydroquinolin-6-yl]- 7.16 (br s, 2H), 6.31 (d, J = 8.4 Hz, 1H), 6-methylthieno[2,3-b]pyridine-2- 4.16-4.12 (m, 1H), 3.77-3.65 (m, 3H), carboxamide 3.48-3.43 (m, 1H), 3.11-3.05 (m, 1H), 3.01-2.89 (m, 1H), 2.84-2.70 (m, 4H), 2.59 (s, 3H), 2.08-1.83 (m, 4H). 365 7-amino-N-[(6S)-2-[(8R)-8- 466 (DMSO-d6, 400 MHz) δ (ppm): 8.65 (s, ++++ ++ amino-2-oxa-6- 1H), 7.81 (br s, 1H), 7.20 (d, J = 8.0 Hz, azaspiro[3.4]octan-6-yl]-5,6,7,8- 1H), 6.92 (br s, 2H), 6.23 (d, J = 8.4 Hz, tetrahydroquinolin-6-yl]-3- 1H), 4.82-4.80 (m, 1 H), 4.47-4.38 (m, methylthieno[2,3-b]pyrazine-6- 3H), 4.16-4.14 (m, 1H), 3.73-3.69 (m, carboxamide 1H), 3.63-3.60 (m, 1H), 3.50-3.42 (m, 2H), 3.06-3.03 (m, 1H), 2.84-2.73 (m, 4H), 2.66 (s, 3H), 2.03-1.83 (m, 4H) 366 7-amino-N-[(6S)-2-[(8S)-8- 466 (DMSO-d6 400 MHz) δ(ppm): 8.65 (s, ++ + amino-2-oxa-6- 1H), 7.81 (br s, 1H), 7.20 (d, J = 8.8 Hz, azaspiro[3.4]octan-6-yl]-5,6,7,8- 1H), 6.92 (br s, 2H), 6.23 (d, J = 8.4 Hz, tetrahydroquinolin-6-yl]-3- 1H), 4.82-4.80 (m, 1 H), 4.47-4.38 (m, methylthieno[2,3-b]pyrazine-6- 3H), 4.16-4.14 (m, 1H), 3.73-3.70 (m, carboxamide 1H), 3.63-3.61 (m, 1H), 3.50-3.42 (m, 2H), 3.06-3.03 (m, 1H), 2.84-2.73 (m, 4H), 2.66 (s, 3H), 2.05-1.83 (m, 4H) 367 3-amino-N-[(6S)-2-[(1R,5S)-9,9- 499 (DMSO-d6 400 MHz) δ(ppm): 8.31 (d, J = ++++ difluoro-2,7- 8.0 Hz, 1H), 7.62 (br s, 1H), 7.32-7.28 diazabicyclo[3.3.1]nonan-7-yl]- (m, 2H), 7.18 (br s, 2H), 6.64 (d, J = 8.4 5,6,7,8-tetrahydroquinolin-6-yl]- Hz, 1H), 4.43-4.32 (m, 2H), 4.18-4.12 6-methylthieno[2,3-b]pyridine-2- (m, 1H), 3.18-3.15 (m, 4H), 2.86-2.80 carboxamide (m, 4H), 2.59 (s, 3H), 2.42-2.40 (m, 1H), 2.08-2.00 (m, 2H), 1.89-1.86 (m, 2H). 368 3-amino-N-[(6S)-2-[(1S,5R)-9,9- 499 (DMSO-d6, 400 MHz) δ(ppm): 8.31 (d, ++++ difluoro-2,7- J = 8.4 Hz, 1H), 7.62 (br s, 1H), 7.32- diazabicyclo[3.3.1]nonan-7-yl]- 7.27 (m, 2H), 7.18 (br s, 2H), 6.64 (d, J = 5,6,7,8-tetrahydroquinolin-6-yl]- 8.8 Hz, 1H), 4.38-4.35 (m, 2H), 4.18- 6-methylthieno[2,3-b]pyridine-2- 4.13 (m, 1H), 3.19-3.14 (m, 4H), 2.82- carboxamide 2.74 (m, 4H), 2.59 (s, 3H), 2.42-2.39 (m, 1H), 2.08-2.00 (m, 2H), 1.89-1.81 (m, 2H). 369 3-amino-N-[(3R)-7-[(3S)-3- 424 (DMSO-d6 400 MHz) δ(ppm): 8.33 (d, ++++ +++ aminopyrrolidin-1-yl]-3,4- J = 8.4 Hz, 1H), 7.48 (br s, 1H), 7.32 (d, dihydro-2H-1-benzopyran-3-yl]- J = 8.4 Hz, 1H), 7.21 (br s, 2H), 6.86 (d, 6-methylthieno[2,3-b]pyridine-2- J = 8.8 Hz, 1H), 6.10 (d, J = 6.4 Hz, 1H), carboxamide 5.90 (s, 1H), 4.30-4.27 (m, 1H), 4.15- 4.13 (m, 1H), 3.82-3.77 (m, 1H), 3.57- 3.51 (m, 1H), 3.29-3.25 (m, 2H), 3.19- 3.13 (m, 1H), 2.89-2.78 (m, 3H), 2.59 (s, 3H), 2.08-2.01 (m, 1H), 1.86 (br s, 2H), 1.71-1.68 (m, 1H). 370 N-[(6S)-2-[(3R,4S)-3-amino-4- 455 (DMSO-d6, 400 MHz) δ(ppm): 8.77 (s, ++ (difluoromethyl)pyrrolidin-1-yl]- 1H), 8.47-8.45 (m, 2H), 7.69 (s, 1H), 5,6,7,8-tetrahydroquinolin-6-yl]- 7.24 (d, J = 8.4 Hz, 1H), 6.59 (s, 1H), 1-ethyl-1H-pyrrolo[2,3- 6.32-6.07 (m, 2H), 4.36-4.30 (m, 2H), b]pyridine-5-carboxamide 4.23-4.17 (m, 1H), 3.66-3.58 (m, 2H), 3.51-3.42 (m, 1H), 3.40-3.30 (m, 1H), 3.06-3.02 (m, 1H), 2.90-2.88 (m, 1H), 2.82-2.79 (m, 2H), 2.72-2.68 (m, 1H), 2.50-2.46 (m, 1H), 2.08-1.93 (m, 3H), 1.90-1.84 (m, 1H), 1.41-1.38 (m, 3H) 371 N-[(6S)-2-[(3S,4R)-3-amino-4- 455 (DMSO-d6, 400 MHz) δ(ppm): 8.77 (s, ++ (difluoromethyl)pyrrolidin-1-yl]- 1H), 8.47-8.45 (m, 2H), 7.64 (s, 1H), 5,6,7,8-tetrahydroquinolin-6-yl]- 7.24 (d, J = 8.4 Hz, 1H), 6.59 (s 1H), 1-ethyl-1H-pyrrolo[2,3- 6.31-6.10 (m, 2H), 4.36-4.30 (m, 2H), b]pyridine-5-carboxamide 4.23-4.17 (m, 1H), 3.69-3.60 (m, 2H), 3.51-3.49 (m, 1H), 3.39-3.34 (m, 1H), 3.06-3.02 (m, 1H), 2.90-2,88 (m, 1H), 2.81-2.79 (m, 2H), 2.72-2.68 (m, 1H), 2.52-2.50 (m, 1H), 2.06-1.85 (m, 4H), 1.41-1.38 (m, 3H) 372 3-amino-N-[(6S)-2-[(3R,4S)-3- 515 (DMSO-d6, 400 MHz) δ(ppm): 8.32-8.29 +++ (difluoromethyl)-4- (m, 2H), 7.59 (d, J = 7.6 Hz, 1H), 7.31 acetamidopyrrolidin-1-yl]- (d, J = 8.4 Hz, 1H), 7.24 (d, J = 8.4 Hz, 5,6,7,8-tetrahydroquinolin-6-yl]- 1H), 7.17 (br s, 2H), 6.36-6.07 (m, 2H), 6-methylthieno[2-3-b]pyridine-2- 4.45-4.41 (m, 1H), 4.16-4.10 (m, 1H), carboxamide 3.73-3.63 (m, 2H), 3.43-3.38 (m, 1H) , 3.21-3.17 (m, 1H), 2.83-2.69 (m, 5H), 2.59 (s, 3H), 2.02-1.99 (m, 1H), 1.90- 1.85 (m, 4H) 373 3-amino-N-[(3R)-7-[3-amino-3- 454 (DMSO-d6, 400 MHz) δ(ppm): 8.33 (d, J = ++++ (methoxymethyl)azetidin-1-yl]- 8.4 Hz, 1H),7.52 (br s, 1H), 7.31 (d, J = 3,4-dihydro-2H-1-benzopyran-3- 8.4 Hz, 1H), 7.23 (br s, 2H), 6.87 (d, J = yl]-6-methylthieno[2,3- 8.0 Hz, 1H), 6.01 (dd, J = 8.4, 2.4 Hz, b]pyridine-2-carboxamide 1H), 5.84 (s, 1H), 4.32-4.25 (m, 1H), 4.15-4.12 (m, 1H),3.81-3.76 (m, 1H), 3.72-3.70 (m, 2H), 3.42 (s, 2H), 3.38- 3.36 (m, 2H), 3.34 (s, 3H),2.90-2.80 (m, 2H), 2.52 (s, 3H), 2.17(br s, 2H) 374 3-amino-N-[(6S)-2-[(3S)-3- 473 (DMSO-d6, 400 MHz) δ(ppm): 8.31 (d, J = +++ (difluoromethyl)piperazin-1-yl]- 8.4 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 5,6,7,8-tetrahydroquinolin-6-yl]- 7.32-7.28 (m, 2H), 7.17 (br s, 2H), 6.67 6-methylthieno[2,3-b]pyridine-2- (d, J = 8.4 Hz, 1H), 6.20-5.91 (m, 1H), carboxamide 4.22-4.10 (m, 2H), 3.95-3.92 (m, 1H), 3.14-3.04 (m, 2H), 2.86-2.69 (m, 7H), 2.59 (s, 3H), 2.02-1.99 (m, 1H), 1.91- 1.84 (m, 1H) 375 3-amino-N-[(6S)-2-[(3R)-3- 473 (DMSO-d6, 400 MHz) δ(ppm): 8.31 (d, J = +++ (difluoromethyl)piperazin-1-yl]- 8.4 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 5,6,7,8-tetrahydroquinolin-6-yl]- 7.32-7.26 (m, 2H), 7.17 (br s, 2H), 6.65 6-methylthieno[2,3-b]pyridine-2- (d, J = 8.4 Hz, 1H), 6.12-5.84 (m, 1H), carboxamide 4.16-4.12 (m, 2H), 3.90-3.87 (m, 1I-1), 3.00-2.97 (m, 2H), 2.85-2.61 (m, 7H), 2.59 (s, 3H), 2.02-1.99 (m, 1H), 1.91- 1.80 (m, 1H) 376 3-amino-N-[(6S)-2-[(3S,4R)-3- 487 (DMSO-d6, 400 MHz) δ(ppm): 8.31 (d, J = +++ (difluoromethyl)-4- 8.0 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), (methylamino)pyrrolidin-1-yl]- 7.31 (d, J = 8.4 Hz, 1H), 7.23-7.17 (m, 5,6,7,8-terahydroquinolin-6-yl]- 3H), 6.32-6.17 (m, 2H), 4.17-4.10 (m, 6-methylthieno[2,3-b]pyridine-2- 1H), 3.64-3.61 (m, 1H), 3.55-3.53 (m, carboxamide 1H), 3.46-3.43 (m, 1H), 3.26-3.18 (m, 2.31 (s, 3H), 2.10-1.99 (m, 2H), 1.90- 1.80 (m, 1H) 377 3-amino-N-[(6S)-2-[(3R,4S)-3- 487 (DMSO-d6, 400 MHz) δ(ppm): 8.31 (d, J = +++ (difluoromethyl)-4- 8.0 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), (methylamino)pyrrolidin-1-yl]- 7.31 (d, J = 8.4 Hz, 1H), 7.24-7.17 (m, 5,6,7,8-tetrahydroquinolin-6-yl]- 3H), 6.32-6.18 (m, 2H), 4.17-4.10 (m, 6-methylthieno[2,3-b]pyridine-2- 1H), 3.66-3.62 (m, 1H), 3.59-3.54 (m, carboxamide 1H), 3.45-3.41 (m, 1H), 3.27-3.16 (m, 2H), 2.83-2.69 (m, 5H), 2.59 (s, 3H), 2.31 (s, 3H), 2.10-1.99 (m, 2H), 1.90- 1.80 (m, 1H) 378 3-amino-N-[(3R)-7-[(3R,4S)-3- 475 (DMSO-d6, 400 MHz) δ(ppm): 8.33 (d, J = +++ amino-4- 8.0 Hz, 1H), 7.55 (d, J = 7.2 Hz, 1H), (difluoromethyl)pyrrolidin-1-yl]- 7.29-7.27 (m, 2H), 7.23 (br s, 2H), 6.34- 2H,3H,4H-pyrano[2,3-b]pyridin- 6.05 (m, 2H), 4.30-4.20 (m, 2H), 3.98- 3-yl]-6-methylthieno[2,3- 3.93 (m, 1H), 3.64-3.46 (m, 3H), 3.37- b]pyridine-2-carboxamide 3.34 (m, 1H), 3.02-2.98 (m, 1H), 2.88- 2.79 (m, 2H), 2.59 (s, 3H), 2.51-2.44 (m, 1H), 1.86 (br s, 2H) 379 3-amino-N-[(3R)-7-[(3S,4R)-3- 475 (DMSO-d6, 400 MHz) δ(ppm): 8.33 (d, J = ++ amino-4- 8.4 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), (difluoromethyl)pyrrolidin-1-yl]- 7.33-7.23 (m, 4H), 6.34-6.05 (m, 2H), 2H,3H,4H-pyrano[2,3-b]pyridin- 4.30-4.20 (m, 2H), 3.98-3.93 (m, 1H), 3-yl]-6-methylthieno[2,3- 3.64-3.47 (m, 3H), 3.37-3.34 (m, 1H), b]pyridine-2-carboxamide 3.02-2.98 (m, 1H), 2.88-2.79 (m, 2H), 2.59 (s, 3H), 2.51-2.44 (m, 1H), 1.86 (br s, 2H) 380 3-amino-N-[(6S)-2-[(3R,4S)-3- 474 (DMSO-d6, 400 MHz) δ(ppm): 8.31 (d, J = +++ amino-4- 8.4 Hz, 1H), 8.09 (s, 1H), 7.64 (d, J = (difluoromethyl)pyrrolidin-1-yl]- 7.6 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 5,6,7,8-tetrahydroquinazolin-6- 7.18 (br s, 2H), 6.34-6.06 (m, 1H), 4.15- yl]-6-methylthieno[2,3- 4.10 (m, 1H), 3.79-3.67 (m, 2H), 3.52- b]pyridine-2-carboxamide 3.46 (m, 2H), 3.17-3.13 (m, 1H), 2.84- 2.62 (m, 4H), 2.59 (s, 3H), 2.00-1.83 (m, 4H). 381 3-amino-N-[(6S)-2-[(3S,4R)-3- 474 (DMSO-d6, 400 MHz) δ(ppm): 8.31 (d, J = ++ amino-4- 8.4 Hz, 1H), 8.09 (s, 1H), 7.64 (d, J = (difluoromethyl)pyrrolidin-1-yl]- 7.6 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 5,6,7,8-tetrahydroquinazolin-6- 7.18 (br s, 2H), 6.34-6.06 (m, 1H), 4.15- yl]-6-methylthieno[2,3- 4.10 (m, 1H), 3.79-3.67 (m, 2H), 3.52- b]pyridine-2-carboxamide 3.47 (m, 2H), 3.16-3.12 (m, 1H), 2.84- 2.62 (m, 4H), 2.59 (s, 3H), 2.00-1.83 (m, 4H). 382 3-amino-N-[(6R)-2-[(3S,4R)-3- 474 (DMSO-d6, 400 MHz) δ(ppm): 8.31 (d, J = ++ amino-4- 8.4 Hz, 1H), 8.09 (s, 1H), 7.64 (d, J = (difluoromethyl)pyrrolidin-1-yl]- 7.6 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 5,6,7,8-tetrahydroquinazolin-6- 7.18 (br s, 2H), 6.34-6.05 (m, 1H), 4.14- yl]-6-methylthieno[2,3- 4.10 (m, 1H), 3.80-3.67 (m, 2H), 3.52- b]pyridine-2-carboxamide 3.45 (m, 2H), 3.16-3.12 (m, 1H), 2.85- 2.62 (m, 4H), 2.59 (s, 3H), 2.01-1.83 (m, 4H) 383 3-amino-N-[(6R)-2-[(3R,4S)-3- 474 (DMSO-d6, 400 MHz) δ(ppm): 8.31 (d, J = + amino-4- 8.4 Hz, 1H), 8.10 (s, 1H), 7.64 (d, J = (difluoromethyl)pyrrolidin-1-yl]- 7.6 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 5,6,7,8-tetrahydroquinazolin-6- 7.18 (br s, 2H), 6.35-6.06 (m, 1H), 4.13- yl]-6-methylthieno[2,3- 4.10 (m, 1H), 3.80-3.67 (m, 2H), 3.52- b]pyridine-2-carboxamide 3.47 (m, 2H), 3.17-3.13 (m, 1H), 2.85- 2.62 (m, 4H), 2.59 (s, 3H), 2.01-1.81 (m, 4H) 384 3-amino-N-[(6S)-2-[(3R,4S)-3- 455 (DMSO-d6 400 MHz) δ(ppm): 8.31 (d, J = +++ amino-4- 8.4 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), (fluoromethyl)pyrrolidin-1-yl]- 7.31(d, J = 1H), 7.21-7.17 (m, 5,6,7,8-tetrahydroquinolin-6-yl]- 3H), 6.24 (d, J = 8.4 Hz, 1H), 4.65-4.46 6-methylthieno[2,3-b]pyridine-2- (m, 2H), 4.14-4.11 (m, 1H), 3.65-3.61 carboxamide (m, 2H), 3.30-3.18 (m, 2H), 3.04-3.00 (m, 1H), 2.81-2.68 (m, 4H), 2.59 (s, 3H), 2.33-2.25 (m, 2H), 2.01-1.99 (m, 1H), 1.87-1.82 (m, 1H) 385 3-amino-N-[(6S)-2-[(3S,4R)-3- 455 (DMSO-d6, 400 MHz) δ(ppm): 8.31 (d, J = +++ amino-4- 8.4 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H) (fluoromethyl)pyrrolidin-1-yl]- 7.31 (d, J = 8.4 Hz, 1H), 7.21-7.17 (m, 5,6,7,8-tetrahydroquinolin-6-yl]- 3H), 6.24 (d, J = 8.8 Hz, 1H), 4.67-4.47 6-methylthieno[2,3-b]pyridine-2- (m, 2H), 4.13-4.12 (m, 1H), 3.64-3.62 carboxamide (m, 2H), 3.30-3.17 (m, 2H), 3.04-3.00 (m, 1H), 2.81-2.68 (m, 4H), 2.59 (s, 3H), 2.33-2.28 (m, 2H), 2.01-1.99 (m, 1H), 1.87-1.82 (m, 1H) 386 3-amino-N-[(6S)-2-[(3R)-3- 453 (DMSO-d6 400 MHz) δ(ppm): 8.31 (d, J = +++ amino-3- 8.4 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), (hydroxymethyl)pyrrolidin-1-yl]- 7.31 (d, J = 8.4 Hz, 1H), 7.19-7.17 (m, 5,6,7,8-tetrahydroquinolin-6-yl]- 3H), 6.20 (d, J = 8.4 Hz, 1H), 4.84-4.83 6-methylthieno[2,3-b]pyridine-2- (m, 1H), 4.14-4.11 (m, 1H), 3.46-3.37 carboxamide (m, 3H), 3.10-3.07 (m, 1H), 2.80-2.68 (m, 6H), 2.59 (s, 3H), 1.98-1.77 (m, 5H), 1.70-1.63 (m, 1H) 387 3-amino-N-[(6S)-2-[(3S)-3- 453 (DMSO-d6 400 MHz) δ(ppm): 8.31 (d, J = +++ amino-3- 7.6 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), (hydroxymethyl)pyrrolidin-1-yl]- 7.31 (d, J = 8.4 Hz, 1H), 7.19-7.17 (m, 5,6,7,8-tetrahydroquinolin-6-yl]- 3H), 6.20 (d, J = 8.4 Hz, 1H), 4.85-4.83 6-methylthieno[2,3-b]pyridine-2- (m, 1H), 4.14-4.11 (m, 1H), 3.45-3.38 carboxamide (m, 3H), 3.10-3.07 (m, 1H), 2.80-2.68 (m, 6H), 2.59 (s, 3H), 1.98-1.82 (m, 5H), 1.70-1.63 (m, 1H) 388 3-amino-N-[(6S)-2-[(3R)-3- 467 (DMSO-d6 400 MHz) δ(ppm): 8.31 (d, J = +++ amino-3- 8.0 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), (methoxymethyl)pyrrolidin-1-yl]- 7.42 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 8.4 5,6,7,8-tetrahydroquinolin-6-yl]- Hz 1H), 7.17 (br s, 2H), 6.61 (d, J = 8.0 6-methylthieno[2,3-b]pyridine-2- Hz, 1H), 4.15-4.11 (m, 1H), 4.06 (s, 2H), carboxamide 3.70-3.60 (m, 3H), 2.90-2.74 (m, 4H), 2.60-2.50 (m, 5H), 2.27-2.22 (m, 4H), 2.06-1.99 (m, 1H), 1.91-1.84 (m, 2H), 1.61-1.57 (m, 1H) 389 3-amino-N-[(6S)-2-[(3S)-3- 467 (DMSO-d6, 400 MHz) δ(ppm): 8.31 (d, J = +++ amino-3- 8.4 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), (methoxymethyl)pyrrolidin-1-yl]- 7.42 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.0 5,6,7,8-tetrahydroquinolin-6-yl]- Hz, 1H), 7.18 (br s, 2H), 6.61 (d, J = 8.0 6-methylthieno[2,3-b]pyridine-2- Hz, 1H), 4.16-4.08 (m, 1H), 4.06-4.02 carboxamide (m, 2H), 3.70-3.60 (m, 3H), 2.91-2.74 (m, 4H), 2.59-2.51 (m, 5H), 2.26-2.22 (m, 4H), 2.08-2.01 (m, 1H), 1.93-1.82 (m, 2H), 1.61-1.57 (m, 1H) 390 3-amino-N-[(6S)-2-[(5S,9S)-9- 479 (DMSO-d6, 400 MHz) δ(ppm): 8.30 (d, ++ + amino-1-oxa-7- J = 8.4 Hz, 1H), 7.57 (br s, 1H), 7.31 (d, azaspiro[4.4]nonan-7-yl]- J = 8.0 Hz, 1H), 7.19-7.16 (m, 3H), 6.18 5,6,7,8-tetrahydroquinolin-6-yl]- (d, J = 8.4 Hz, 1H), 4.14-4.09 (m, 1H), 6-methylthieno[2,3-b]pyridine-2- 3.79-3.70 (m, 2H), 3.54-3.50 (m, 1H), carboxamide 3.45-3.42 (m, 1H), 3.30-3.28 (m, 1H), 3.20-3.14 (m, 2H), 2.81-2.68 (m, 4H), 2.59 (s, 3H), 2.21-2.14 (m, 1H), 2.01- 1.82 (m, 5H), 1.72-1.65 (m, 1H). 391 3-amino-N-[(6S)-2-[(5S,9R)-9- 479 (DMSO-d6, 400 MHz) δ (ppm): 8.31 (d, +++ ++ amino-1-oxa-7- J = 8.4 Hz, 1H), 7.56 (br s, 1H), 7.31 (d, azaspiro[4.4]nonan-7-yl]- J = 8.0 Hz, 1H), 7.19-7.16 (m, 3H), 6.18 5,6,7,8-tetrahydroquinolin-6-yl]- (d, J = 8.4 Hz, 1H), 4.16-4.12 (m, 1H), 6-methylthieno[2,3-b]pyridine-2- 3.86-3.80 (m, 2H), 3.59-3.52 (m, 2H), carboxamide 3.28-3.21 (m, 2H), 2.97-2.92 (m, 1H), 2.81-2.68 (m, 4H), 2.59 (m, 3H), 2.00- 1.80 (m, 8H). 392 3-amino-N-[(6S)-2-[(5R,9R)-9- 479 (DMSO-d6 400 MHz) δ (ppm): 8.31 (d, ++ + amino-1-oxa-7- J = 8.4 Hz, 1H), 7.57 (br s, 1H), 7.31 (d, azaspiro[4.4]nonan-7-yl]- J = 8.0 Hz, 1H), 7.19-7.16 (m, 3H), 6.19 5,6,7,8-tetrahydroquinolin-6-yl]- (d, J = 8.4 Hz, 1H), 4.16-4.12 (m, 1H), 6-methylthieno[2,3-b]pyridine-2- 3.77-3.72 (m, 2H), 3.53-3.49 (m, 1H), carboxamide 3.44-3.41 (m, 1H), 3.30-3.28 (m, 1H), 3.20-3.16 (m, 2H), 2.81-2.68 (m, 4H), 2.59 (m, 3H), 2.21-2.15 (m, 2H), 2.01- 1.98 (m, 1H), 1.92-1.82 (m, 3H), 1.72- 1.68 (m, 1H). 393 3-amino-N-[(6S)-2-[(5R,9S)-9- 479 (DMSO-d6, 400 MHz) δ (ppm): 8.30 (d, +++ + amino-1-oxa-7- J = 8.0 Hz, 1H), 7.57 (br s, 1H), 7.31 (d, azaspiro[4.4]nonan-7-yl]- J = 8.4 Hz, 1H), 7.19-7.16 (m, 3H), 6.18 5,6,7,8-tetrahydroquinolin-6-yl]- (d, J = 8.4 Hz, 1H), 4.14-4.11 (m, 1H), 6-methylthieno[2,3-b]pyridine-2- 3.82-3.78 (m, 2H), 3.57-3.53 (m, 2H), carboxamide 3.27-3.23 (m, 2H), 2.98-2.93 (m, 1H), 2.77-2.71 (m, 4H), 2.59 (m, 3H), 1.98- 1.86 (m, 8H). 394 N-[(6S)-2-[(3aR,6aS)-3a-amino- 465 (DMSO-d6, 400 MHz) δ (ppm): 8.31 (d, J = +++ hexahydro-1H-furo[3,4-c]pyrrol- 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 5-yl]-5,6,7,8-tetrahydroquinolin- 7.31 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 8.4 6-yl]-3-amino-6- Hz, 1H), 7.17 (br s, 2H), 6.28 (d, J = 8.4 methylthieno[2,3-b]pyridine-2- Hz, 1H), 4.14-4.08 (m, 1H), 4.06-4.02 carboxamide (m, 1H), 3.66-3.55 (m, 5H), 3.30-3.24 (m, 3H), 2.88-2.69 (m, 4H), 2.59 (s, 3H), 2.01-1.99 (m, 1H), 1.91-1.80 (m, 1H) 395 N-[(6S)-2-[(3aS,6aR)-3a-amino- 465 (DMSO-d6, 400 MHz) δ (ppm): 8.31 (d, J = +++ hexahydro-1H-furo[3,4-c]pyrrol- 8.4 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), 5-yl]-5,6,7,8-tetrahydroquinolin- 7.31 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 8.4 6-yl]-3-amino-6- Hz, 1H), 7.17 (br s, 2H), 6.28 (d, J = 8.4 methylthieno[2,3-b]pyridine-2- Hz, 1H), 4.14-4.08 (m, 1H), 4.06-4.02 carboxamide (m, 1H), 3.66-3.54 (m, 5H), 3.31-3.23 (m, 3H), 2.84-2.69 (m, 4H), 2.59 (s, 3H), 2.09-1.94 (m, 3H), 1.91-1.80 (m, 1H) 396 3-amino-6-methyl-N-[(6S)-2- 479 (DMSO-d6 400 MHz) δ(ppm): 8.31 (d, J = +++ [(1R,5S,9r)-9-amino-3-oxa-7- 8.0 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), azabicyclo[3.3.1]nonan-7-yl]- 7.31 (d, J = 8.4 Hz, 1H), 7.19-7.17 (m, 5,6,7,8-tetrahydroquinolin-6- 3H), 6.51 (d, J = 8.8 Hz, 1H), 4.29-4.22 yl]thieno[2,3-b]pyridine-2- (m, 2H), 4.19-4.06 (m, 3H), 3.51 (d, J = carboxamide 11.2 Hz, 2H), 3.14-3.05 (m, 3H), 2.83- 2.68 (m, 4H), 2.59 (s, 3H), 2.17 (br s, 2H), 2.01-1.99 (m, 1H), 1.89-1.82 (m, 1H), 1.61-1.59 (m, 2H) 397 3-amino-6-methyl-N-[(6S)-2- 479 (DMSO-d6, 400 MHz) δ(ppm): 8.31 (d, J = +++ [(1R,5S,9s)-9-amino-3-oxa-7- 8.4 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H) , azabicyclo[3.3.1]nonan-7-yl]- 7.31 (d, J = 8.0 Hz, 1H), 7.22-7.17 (m, 5,6,7,8-tetrahydroquinolin-6- 3H), 6.48 (d, J = 8.8 Hz, 1H),4.16-4.03 yl]thieno[2,3-b]pyridine-2- (m, 1H), 3.92-3.87 (m, 4H), 3.60-3.57 carboxamide (m, 2H), 3.34-3.33 (m, 2H), 3.16 (s, 1H), 2.83-2.68 (m, 4H), 2.59 (s, 3H), 2.01- 1.99 (m, 1H), 1.89-1.82 (m, 1H), 1.76- 1.74 (m, 2H) 398 3-amino-N-[(6S)-2-[(7R)-7- 465 (DMSO-d6, 400 MHz) δ(ppm): 8.31 (d, J = +++ amino-5-oxa-2- 8.0 Hz, 1H), 7.60 (d, J = 6.8 Hz, 1H), azaspiro[3.4]octan-2-yl]-5,6,7,8- 7.31 (d, J = 8.0 Hz, 1H), 7.24-7.17 (m, tetrahydroquinolin-6-yl]-6- 3H), 6.20 (d, J = 8.4 Hz, 1H), 4.14-4.07 methylthieno[2,3-b]pyridine-2- (m, 1H), 3.99-3.81 (m, 4H), 3.52-3.40 carboxamide (m, 3H), 2.82-2.69 (m, 4H), 2.59 (s, 3H), 2.25-2.20 (m, 1H), 1.98-1.79 (m, 4H) 399 3-amino-N-[(6S)-2-[(7S)-7- 465 (DMSO-d6, 400 MHz) δ(ppm): 8.31 (d, J = ++++ amino-5-oxa-2- 8.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), azaspiro[3.4]octan-2-yl]-5,6,7,8- 7.31 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 8.0 tetrahydroquinolin-6-yl]-6- Hz, 1H), 7.18 (br s, 2H), 6.20 (d, J = 8.0 methylthieno[2,3-b]pyridine-2- Hz, 1H), 4.18-4.09 (m, 1H), 4.02-4.00 carboxamide (m, 1H), 3.91-3.81 (m, 4H), 3.53-3.40 (m, 2H), 2.82-2.69 (m, 4H), 2.59 (s, 3H), 2.24-2.20 (m, 1H), 1.98-1.80 (m, 3H), 1.70 (br s, 2H) 400 N-[(6S)-2-[(3R,4R)-3-amino-4- 449 (DMSO-d6 400 MHz) δ(ppm): 8.77 (s, ++ (methoxymethyl)pyrrolidin-1-yl]- 1H), 8.47-8.45 (m, 2H), 7.69 (d, J = 3.6 5,6,7,8-tetrahydroquinolin-6-yl]- Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 6.59 1-ethyl-1H-pyrrolo[2,3- (d, J = 3.6 Hz, 1H), 6.21 (d, J = 8.4 Hz, b]pyridine-5-carboxamide 1H), 4.36-4.30 (m, 2H), 4.22-4.17 (m, 1H), 3.60-3.33 (m, 5H), 3.28 (s, 3H), 3.23-3.18 (m, 2H), 2.88-2.81 (m, 1H), 2.80-2.77 (m, 2H), 2.71-2.67 (m, 1H), 2.41-2.38 (m, 1H), 2.10-2.05 (m, 1H), 1.88-1.82 (m, 1H), 1.59 (br s, 2H), 1.41- 1.38 (m, 4H) 401 N-[(6S)-2-[(3S,4S)-3-amino-4- 449 (DMSO-d6, 400 MHz) δ(ppm): 8.77 (d, J = ++ (methoxymethyl)pyrrolidin-1-yl]- 2.0 Hz, 1H), 8.47-8.45 (m, 2H), 7.68 5,6,7,8-tetrahydroquinolin-6-yl]- (d, J = 3.6 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1-ethyl-1H-pyrrolo[2,3- 1H), 6.59 (d, J = 3.2 Hz, 1H), 6.21 (d, J = b]pyridine-5-carboxamide 8.4 Hz, 1H), 4.36-4.30 (m, 2H), 4.18- 4.13 (m, 1H), 3.60-3.35 (m, 5H), 3.28 (s, 3H), 3.22-3.17 (m, 2H), 2.88-2.86 (m, 1H), 2.78-2.77 (m, 2H), 2.71-2.67 (m, 1H), 2.41-2.37 (m, 1H), 2.11-2.04 (m, 1H), 1.90-1.80 (m, 1H), 1.55 (br s, 2H), 1.41-1.38 (m, 3H) 402 1-ethyl-N-[(6S)-2-[(3S,4S)-3- 449 (DMSO-d6, 400 MHz) δ(ppm): 8.77 (d, J = ++ methoxy-4- 2.0 Hz, 1H), 8.47-8.45 (m, 2H), 7.69 (methylamino)pyrrolidin-1-yl]- (d, J = 3.6 Hz, 1H), 7.21 (d, J = 8.4 Hz, 5,6,7,8-tetrahydroquinolin-6-yl]- 1H), 6.59 (d, J = 3.6 Hz, 1H), 6.25 (d, J = 1H-pyrrolo[2,3-b]pyridine-5- 8.4 Hz, 1H), 4.36-4.30 (m, 2H), 4.22- carboxamide 4.18 (m, 1H), 3.78-3.77 (m, 1H), 3.54- 3.22 (m, 7H), 3.13-3.11 (m, 1H), 2.88- 2.87 (m, 1H), 2.81-2.78 (m, 2H), 2.72- 2.68 (m, 1H), 2.32 (s, 3H), 2.11-2.06 (m, 1H), 1.90-1.80 (m, 2H), 1.41-1.38 (m, 3H) 403 N-[(6S)-2-[(8R)-8-amino-2-oxa- 447 (DMSO-d6, 400 MHz) δ(ppm): 8.77 (s, + 6-azaspiro[3.4]octan-6-yl]- 1H), 8.47-8.45 (m, 2H), 7.68 (d, J = 3.2 5,6,7,8-tetrahydroquinolin-6-yl]- Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 6.59 1-ethyl-1H-pyrrolo[2,3- (d, J = 3.6 Hz, 1H), 6.23 (d, J = 8.4 Hz, b]pyridine-5-carboxamide 1H), 4.81(d, J = 6.0 Hz, 1H), 4.47-4.30 (m, 5H), 4.22-4.13 (m, 1H), 3.72-3.60 (m, 2H), 3.48-3.36 (m, 3H), 3.06-3.04 (m, 1H), 2.92-2.73 (m, 4H), 2.08-2.02 (m, 2H), 1.88-1.82 (m, 1H), 1.41-1.38 (m, 3H) 404 N-[(6S)-2-[(8S)-8-amino-2-oxa- 447 (DMSO-d6, 400 MHz) δ(ppm): 8.76 (s, ++ 6-azaspiro[3.4]octan-6-yl]- 1H), 8.47-8.45 (m, 2H), 7.68 (d, J = 3.6 5,6,7,8-tetrahydroquinolin-6-yl]- Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 6.59 1-ethyl-1H-pyrrolo[2,3- (d, J = 3.6 Hz, 1H), 6.23 (d, J = 8.4 Hz, b]pyridine-5-carboxamide 1H), 4.81(d, J = 6.0 Hz, 1H), 4.48-4.30 (m, 5H), 4.22-4.13 (m, 1H), 3.73-3.57 (m, 2H), 3.50-3.37 (m, 3H), 3.06-3.04 (m, 1H), 2.92-2.68 (m, 4H), 2.08-2.02 (m, 2H), 1.88-1.82 (m, 1H), 1.41-1.38 (m, 3H) 405 3-amino-N-[(6S)-2-[(4R,5S)-4- 479 (DMSO-d6, 400 MHz) δ(ppm): 8.30 (d, J = +++ amino-1-oxa-7- 8.4 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), azaspiro[4.4]nonan-7-yl]- 7.31 (d, J = 8.0 Hz, 1H), 7.21-7.16 (m, 5,6,7,8-tetrahydroquinolin-6-yl]- 3H), 6.23 (d, J = 8.4 Hz, 1H), 4.15-4.09 6-methylthieno[2,3-b]pyridine-2- (m, 1H), 3.85-3.49 (m, 4H), 3.30-3.28 carboxamide (m, 3H), 2.77-2.70 (m, 4H), 2.59 (s, 3H), 2.23-2.15 (m, 2H), 2.08-1.84 (m, 5H), 1.76-1.68 (m, 1H) 406 3-amino-N-[(6S)-2-[(4S,5R)-4- 479 (DMSO-d6, 400 MHz) δ(ppm): 8.31 (d, J = ++ amino-1-oxa-7- 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), azaspiro[4.4]nonan-7-yl]- 7.31 (d, J = 8.4 Hz, 1H), 7.21-7.17 (m, 5,6,7,8-tetrahydroquinolin-6-yl]- 3H), 6.23 (d, J = 8.4 Hz, 1H), 4.15-4.09 6-methylthieno[2,3-b]pyridine-2- (m, 1H), 3.83-3.47 (m, 4H), 3.31-3.22 carboxamide (m, 3H), 2.81-2.69 (m, 4H), 2.59 (s, 3H), 2.23-2.17 (m, 2H), 2.01-1.81 (m, 5H), 1.73-1.68 (m, 1H) 407 3-amino-N-[(6S)-2-[(4S,5S)-4- 479 (DMSO-d6 400 MHz) δ(ppm): 8.31 (d, J = +++ amino-1-oxa-7- 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), azaspiro[4.4]nonan-7-yl]- 7.31 (d, J = 8.4 Hz, 1H), 7.20-7.17 (m, 5,6,7,8-tetrahydroquinolin-6-yl]- 3H), 6.22 (d, J = 8.0 Hz, 1H), 4.18-4.09 6-methylthieno[2,3-b]pyridine-2- (m, 1H), 3.82-3.79 (m, 1H), 3.71-3.66 carboxamide (m, 1H), 3.53-3.48 (m, 1H), 3.34-3.25 (m, 4H), 2.80-2.64 (m, 4H), 2.59 (s, 3H), 2.20-2.07 (m, 3H), 2.03-1.97 (m, 1H), 1.89-1.76 (m, 3H), 1.70-1.62(m, 1H) 408 3-amino-N-[(6S)-2-[(4R,5R)-4- 479 (DMSO-d6, 400 MHz) δ(ppm): 8.31 (d, J = +++ amino-1-oxa-7- 8.4 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), azaspiro[4.4]nonan-7-yl]- 7.31 (d, J = 8.0 Hz, 1H), 7.20-7.17 (m, 5,6,7,8-tetrahydroquinolin-6-yl]- 3H), 6.22 (d, J = 8.8 Hz, 1H), 4.18-4.09 6-methylthieno[2,3-b]pyridine-2- (m, 1H), 3.84-3.79 (m, 1H), 3.71-3.66 carboxamide (m, 1H), 3.54-3.50 (m, 1H), 3.34-3.25 (m, 4H), 2.76-2.68 (m, 4H), 2.59 (s, 3H), 2.18-2.07 (m, 2H), 2.03-1.98 (m, 2H), 1.86-1.76 (m, 2H), 1.70-1.64 (m, 1H) 409 3-amino-N-[(3R)-7-[(4R,5S)-4- 480 (DMSO-d6 400 MHz) δ(ppm): 8.33 (d, J = ++++ amino-1-oxa-7- 8.4 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), azaspiro[4.4]nonan-7-yl]-3,4- 7.32 (d, J = 8.0 Hz, 1H), 7.23-7.17 (m, dihydro-2H-1-benzopyrnonan-3-yl]- 2H), 6.87 (d, J = 8.0 Hz, 1H), 6.11 (d, J = 6-methylthieno[2,3-b]pyridine-2- 6.8 Hz, 1H), 5.92 (s, 1H), 4.28-4.26 carboxamide (m, 1H), 4.15-4.13 (m, 1H), 3.82-3.68 (m, 3H), 3.54-3.52 (m, 1H), 3.27-3.21 (m, 3H), 2.99-2.96 (m, 1H), 2.86-2.83 (m, 2H), 2.59 (s, 3H), 2.19-2.12 (m, 1H), 2.03-1.96 (m, 1H), 1.86-1.82 (m, 1H), 1.70-1.64 (m, 1H) 410 3-amino-N-[(3R)-7-[(4R,5R)-4- 480 (DMSO-d6, 400 MHz) δ(ppm): 8.33 (d, J = ++++ amino-1-oxa-7- 8.4 Hz, 1H), 7.51 (d, J = 7.2 Hz, 1H), azaspiro[4.4]nonan-7-yl]-3,4- 7.32 (d, J = 8.4 Hz, 1H), 7.22 (br s, 2H), dihydro-2H-1-benzopyran-3-yl]- 6.87 (d, J = 8.0 Hz, 1H), 6.09 (d, J = 6.8 6-methylthieno[2,3-b]pyridine-2- Hz, 1H), 5.91 (s, 1H), 4.28-4.26 (m, 1H), carboxamide 4.15-4.13 (m, 1H), 3.84-3.78 (m, 2H), 3.69-3.67 (m, 1H), 3.27-3.21 (m, 3H), 3.05-3.02 (m, 1H), 2.89-2.83 (m, 2H), 2.59 (s, 3H), 2.17-2.12 (m, 2H), 1.93- 1.79 (m, 3H), 1.70-1.63 (m, 1H) 411 3-amino-N-[(3R)-7-[(4S,5S)-4- 480 (DMSO-d6, 400 MHz) δ(ppm): 8.32 (d, J = ++++ amino-1-oxa-7- 8.0 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), azaspiro[4.4]nonan-7-yl]-3,4- 7.32 (d, J = 8.4 Hz, 1H), 7.22 (br s, 2H), dihydro-2H-1-benzopyran-3-yl]- 6.86 (d, J = 8.4 Hz, 1H), 6.11-6.08 (m, 6-methylthieno[2,3-b]pyridine-2- 1H), 5.90 (s, 1H), 4.31-4.23 (m, 1H), carboxamide 4.15-4.12 (m, 1H), 3.84-3.76 (m, 2H), 3.71-3.65 (m, 2H), 3.41-3.20 (m, 3H), 3.04-3.02 (m, 1H), 2.85-2.81 (m, 2H), 2.58 (s, 3H), 2.17-2.11 (m, 2H), 1.81- 1.63 (m, 2H) 412 3-amino-N-[(3R)-7-[(4S,5R)-4- 480 (MeOH-d4, 400 MHz) δ(ppm): 8.22 (d, J = amino-1-oxa-7- 8.4 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), azaspiro[4.4]nonan-7-yl]-3,4- 6.92 (d, J = 8.4 Hz, 1H), 6.24-6.22 (m, dihydro-2H-1-benzopyran-3-yl]- 1H), 6.07 (s, 1H), 4.46-4.44 (m, 1H), 6-methylthieno[2,3-b]pyridine-2- 4.25-4.22 (m, 1H), 4.05-3.95 (m, 1H), carboxamide 3.94-3.90 (m, 2H), 3.61 (d, J = 10.4 Hz, 1H), 3.54-3.52 (m, 1H), 3.41-3.33 (m, 2H), 3.24 (d, J = 10.4 Hz, 1H), 2.97-2.95 (m, 1H), 2.88-2.86 (m, 1H), 2.65 (s, 3H), 2.49-2.41 (m, 1H), 2.07-2.02 (m, 2H), 1.99-1.90 (m, 1H) 413 3-amino-N-[(3R)-5-fluoro-7- 498 (DMSO-d6, 400 MHz) δ(ppm): 8.33 (d, ++++ ++ [(1R)-1-methyl-9-oxa-3,7- J = 8.4 Hz, 1H), 7.59 (br s, 1H), 7.32 (d, diazabicyclo[3.3.1]nonan-3-yl]- J = 8.0 Hz, 1H), 7.24 (br s, 2H), 6.46 (d, 3,4-dihydro-2H-1-benzopyran-3- J = 14.8 Hz, 1H), 6.24 (s, 1H), 4.32-4.28 yl]-6-methylthieno[2,3- (m, 1H), 4.20-4.17 (m, 1H), 3.89-3.84 b]pyridine-2-carboxamide (m, 1H), 3.79-3.63 (m, 3H), 3.00-2.85 (m, 5H), 2.79-2.61 (m, 3H), 2.55 (s, 3H), 0.99 (s, 3H). 414 3-amino-N-[(3R)-5-fluoro-7- 498 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, +++ ++ [(1S)-1-methyl-9-oxa-3,7- J = 8.4 Hz, 1H), 7.59 (br s, 1H), 7.32 (d, diazabicyclo[3.3.1]nonan-3-yl]- J = 8.0 Hz, 1H), 7.24 (br s, 2H), 6.46 (d, 3,4-dihydro-2H-1-benzopyran-3- J = 14.8 Hz, 1H), 6.24 (s, 1H), 4.29-4.27 yl]-6-methylthieno[2,3- (m, 1H), 4.20-4.17 (m, 1H), 3.89-3.84 b]pyridine-2-carboxamide (m, 1H), 3.78-3.64 (m, 3H), 3.00-2.85 (m, 5H), 2.79-2.61 (m, 3H), 2.59 (s, 3H), 2.20-2.10 (m, 1H), 0.99 (s, 3H). 415 3-amino-N-[(3R)-7-[(3R,4R)-3- 490 (DMSO-d6, 400 MHz) δ (ppm): 8.32 (d, ++++ ++ amino-4-methoxypyrrolidin-1- J = 8.0 Hz, 1H), 7.58 (br s, 1H), 7.32 (d, yl]-5,6-difluoro-3,4-dihydro-2H- J = 8.0 Hz, 1H), 7.23 (s, 2H), 6.03 (d, J = 1-benzopyran-3-yl]-6- 6.4 Hz, 1H), 4.30-4.26 (m, 1H), 4.17- methylthieno[2,3-b]pyridine-2- 4.15 (m, 1H), 3.88-3.83 (m, 2H), 3.77- carboxamide 3.73 (m, 1H), 3.68-3.57 (m, 2H), 3.32- 3.20 (m, 5H), 2.81-2.78 (m, 1H), 2.72- 2.66 (m, 1H), 2.59 (s, 3H). 416 3-amino-N-[(3R)-7-[(3S,4S)-3- 490 (DMSO-d6, 400 MHz) δ (ppm): 8.32 (d, ++++ ++ amino-4-methoxypyrrolidin-1- J = 8.0 Hz, 1H), 7.58 (br s, 1H), 7.31 (d, yl]-5,6-difluoro-3,4-dihydro-2H- J = 8.0 Hz, 1H), 7.23 (s, 2H), 5.97 (d, J = 1-benzopyran-3-yl]-6- 7.6 Hz, 1H), 4.30-4.26 (m, 1H), 4.16- methylthieno[2,3-b]pyridine-2- 4.14 (m, 1H), 3.87-3.82 (m, 1H), 3.72- carboxamide 3.67 (m, 2H), 3.57-3.53 (m, 2H), 3.42- 3.15(m, 5H), 2.81-2.78 (m, 1H), 2.72- 2.66 (m, 1H), 2.59 (s, 3H). 417 3-amino-N-[(2S)-7,8-difluoro-6- 458 (DMSO-d6, 400 MHz) δ (ppm): 8.32 (d, ++ + (piperazin-1-yl)-1,2,3,4- J = 8.0 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), tetrahydronaphthalen-2-yl]-6- 7.32 (d, J = 8.0 Hz, 1H), 7.24 (br, 2H), methylthieno[2,3-b]pyridine-2- 6.59 (d, J = 7.6 Hz, 1H), 4.17-4.11 (m, carboxamide 1H), 3.00-2.75 (m, 11H), 2.68-2.59 (m, 1H), 2.43 (s, 3H) 2.41 (br s, 1H) 1.98- 1.96 (m, 1H), 1.81-1.71 (s, 1H). 418 3-amino-N-[(2R)-7,8-difluoro-6- 458 (DMSO-d6 400 MHz) δ (ppm): 8.32 (d, +++ ++ (piperazin-1-yl)-1,2,3,4- J = 8.0 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), tetrahydronaphthalen-2-yl]-6- 7.32 (d, J = 8.0 Hz, 1H), 7.24 (br, 2H), methylthieno[2,3-b]pyridine-2- 6.59 (d, J = 7.6 Hz, 1H), 4.17-4.11 (m, carboxamide 1H), 3.00-2.75 (m, 11H), 2.68-2.60 (m, 1H), 2.59 (s, 3H) 1.98-1.96 (m, 1H), 1.81-1.71 (s, 1H). 419 3-amino-N-[(6S)-2-[(2R,3R)-3- 467 (DMSO-d6 400 MHz) δ(ppm): 8.31 (d, J = +++ amino-2- 8.0 Hz, 1H),7.60 (br s, 1H), 7.31 (d, J = (methoxymethyl)pyrrolidin-1-yl]- 8.0 Hz, 1H), 7.20 (d, J = 8.8 Hz, 5,6,7,8-tetrahydroquinolin-6-yl]- 1H),7.17 (br s, 2H), 6.27 (d, J = 8.4 Hz, 6-methylthieno[2,3-b]pyridine-2- 1H), 4.16-4.10 (m, 1H), 3.81-3.78 (m, carboxamide 1H), 3.52-3.40 (m, 4H),3.34 (s, 3H), 3.28-3.22 (m, 1H), 2.82-2.73 (m, 4H), 2.59 (s, 3H), 2.15-2.10 (m, 1H), 2.08- 2.02 (m, 1H), 1.92-1.86 (m, 1H),1.68- 1.65 (m, 1H) 420 3-amino-N-[(6S)-2-[(2S,3S)-3- 467 (DMSO-d6, 400 MHz) δ(ppm): 8.31 (d, J = ++++ amino-2- 8.0 Hz, 1H),7.58 (br s, 1H), 7.31 (d, J = (methoxymethyl)pyrrolidin-1-yl]- 8.4 Hz, 1H), 7.20 (d, J = 8.8 Hz, 5,6,7,8-tetrahydroquinolin-6-yl]- 1H),7.17 (br s, 2H), 6.28 (d, J = 8.4 Hz, 6-methylthieno[2,3-b]pyridine-2- 1H), 4.18-4.12 (m, 1H), 3.81-3.77 (m, carboxamide 1H), 3.50-3.40 (m, 4H),3.28 (s, 3H), 3.23-3.21 (m, 1H), 2.83-2.71 (m, 4H), 2.59 (s, 3H), 2.15-2.10 (m, 1H), 2.06- 2.02 (m, 1H), 1.94-1.84 (m, 1H),1.68- 1.65 (m, 1H) 421 N-[(6S)-2-[(3R,4S)-3-amino-4- 473 (DMSO-d6 400 MHz) δ(ppm): 8.76 (s, +++ (trifluoromethyl)pyrrolidin-1-yl]- 1H),8.46-8.45 (m, 2H), 7.68 (br s, 1H), 5,6,7,8-tetrahydroquinolin-6-yl]- 7.25 (d, J = 8.0 Hz, 1H),6.59 (d, J = 3.6 1-ethyl-1H-pyrrolo[2,3- Hz, 1H), 6.31 (d, J = 8.4 Hz, 1H), 4.32 b]pyridine-5-carboxamide (dd, J = 14.4, 3.2 Hz, 2H), 4.22-4.18 (m, 1H), 3.77-3.67 (m, 3H), 3.49-3.45 (m, 1H),3.11-3.07 (m, 1H), 3.06-2.89 (m, 2H), 2.82-2.78 (m, 2H), 2.72-2.66 (m, 1H),2.12-1.98 (m, 3H), 1.93-1.83 (m, 1H), 1.39(t, J = 8.4 Hz, 3H) 422 N-[(6S)-2-[(3S,4R)-3-amino-4- 473 (DMSO-d6, 400 MHz) δ(ppm): 8.76 (s, ++ (trifluoromethyl)pyrrolidin-1-yl]- 1H),8.46-8.45 (m, 2H), 7.68 (br s, 1H), 5,6,7,8-tetrahydroquinolin-6-yl]- 7.25 (d, J = 8.4 Hz, 1H),6.58 (d, J = 1-ethyl-1H-pyrrolo[2,3- 3.6 Hz, 1H), 6.31 (d, J = 8.4 Hz, 1H), b]pyridine-5-carboxamide 4.32 (dd, J = 14.4, 3.2 Hz, 2H), 4.22- 4.18 (m, 1H), 3.77-3.68 (m, 3H), 3.47- 3.43 (m, 1H),3.11-3.07 (m, 1H), 3.01- 2.89 (m, 2H), 2.82-2.78 (m, 2H), 2.72- 2.70 (m, 1H),2.12-2.06 (m, 1H), 1.96- 1.82 (m, 3H), 1.39(t, J = 8.4 Hz, 3H) 423 3-amino-N-[(3R)-7-[(3R,4R)-3- 456 (DMSO-d6, 400 MHz) δ(ppm): 8.32 (d, J = ++++ amino-4- 8.0 Hz, 1H),7.50 (br s, 1H), 7.31 (d, J = (fluoromethyl)pyrrolidin-1-yl]- 8.4 Hz, 1H), 7.22 (br s, 2H), 6.87(d, J = 3,4-dihydro-2H-1-benzopyran-3- 8.4 Hz, 1H), 6.09 (d, J = 8.4 Hz, 1H), yl]-6-methylthieno[2,3- 5.90 (s, 1H), 4.80-4.45 (m, 2H), 4.27- b]pyridine-2-carboxamide 4.21 (m, 1H), 4.15-4.10 (m, 1H), 3.81- 3.76 (m,1H), 3.61-3.60 (m, 1H), 3.34- 3.32 (m, 1H), 3.28-3.26 (m, 1H), 3.16- 3.12 (m, 1H), 2.97-2.95 (m, 1H), 2.89- 2.82 (m, 2H), 2.59-2.57 (m, 4H), 1.89 (br s, 2H) 424 3-amino-N-[(3R)-7-[(3S,4S)-3- 456 (DMSO-d6 400 MHz) δ(ppm): 8.32 (d, J = ++++ amino-4- 8.0 Hz, 1H),7.50 (br s, 1H), 7.31 (d, J = (fluoromethyl)pyrrolidin-1-yl]- 8.0 Hz, 1H), 7.22 (br s, 2H), 6.87 (d, J = 3,4-dihydro-2H-1-benzopyran-3- 8.4 Hz, 1H), 6.09 (d, J = 6.8 Hz, 1H), yl]-6-methylthieno[2,3- 5.90 (s, 1H), 4.81-4.46 (m, 2H), 4.29- b]pyridine-2-carboxamide 4.23 (m, 1H), 4.15-4.12 (m, 1H), 3.81- 3.76 (m,1H), 3.61-3.60 (m, 1H), 3.42- 3.34 (m, 1H), 3.28-3.26 (m, 1H), 3.16- 3.12 (m, 1H), 2.97-2.95 (m, 1H), 2.89- 2.83 (m, 2H), 2.59-2.57 (m, 4H), 1.86 (br s, 2H) 425 N-[(3R)-7-[(3aS,6R,6aS)-6- 466 (DMSO-d6, 400 MHz) δ(ppm): 8.33 (d, J = ++++ amino-hexahydro-2H-furo[3,2- 8.0 Hz, 1H),7.51 (br s, 1H), 7.32 (d, J = b]pyrrol-4-yl]-3,4-dihydro-2H-1- 8.4 Hz, 1H), 7.22 (br s, 2H), 6.89 (d, J = benzopyran-3-yl]-3-amino-6- 8.0 Hz, 1H), 6.18 (dd, J = 8.0, 2.0 Hz, methylthieno[2,3-b]pyridine-2- 1H), 5.98 (s, 1H), 4.36-4.25 (m, 2H), carboxamide 4.16-4.15 (m, 2H),3.83-3.78 (m, 1H), 3.74-3.70 (m, 1H), 3.61-3.57 (m, 1H), 3.04-3.01 (m, 1H),2.86-2.83 (m, 3H), 2.59 (s, 3H), 2.08-2.02 (m, 1H), 1.88- 1.84 (m, 1H), 1.80(br s, 2H) 426 N-[(3R)-7-[(3aR,65,6aR)-6- 466 (DMSO-d6, 400 MHz) δ (ppm): 8.33 (d, J = ++++ amino-hexahydro-2H-furo[3,2- 8.4 Hz, 1H),7.52 (br s, 1H), 7.31 (d, J = b]pyrrol-4-yl]-3,4-dihydro-2H-1- 8.0 Hz, 1H), 7.22 (br s, 2H), 6.89 (d, J = benzopyran-3-yl]-3-amino-6- 8.4 Hz, 1H), 6.18 (dd, J = 8.0, 2.0 Hz, methylthieno[2,3-b]pyridine-2- 1H), 5.98 (s, 1H), 4.36-4.25 (m, 2H), carboxamide 4.16-4.13 (m, 2H),3.83-3.78 (m, 1H), 3.74-3.70 (m, 1H), 3.61-3.57 (m, 1H), 3.04-3.01 (m, 1H),2.87-2.82 (m, 3H), 2.59 (s, 3H), 2.08-2.02 (m, 1H), 1.88- 1.84 (m, 1H), 1.76(br s, 2H) 427 3-amino-N-[(6S)-2-[(3R,4S)-4- 467 (DMSO-d6, 400 MHz) δ (ppm): 8.31 (d, J = +++ amino-3-methoxy-3- 8.0 Hz, 1H),7.57 (br s, 1H), 7.31 (d, J = methylpyrrolidin-1-yl]-5,6,7,8- 8.4 Hz, 1H), 7.18 (d, J = 8.8 Hz, tetrahydroquinolin-6-yl]-6- 1H),7.16 (br s, 2H), 6.21 (d, J = 8.4 Hz, methylthieno[2,3-b]pyridine-2- 1H), 4.17-4.10 (m, 1H), 3.78-3.75 (m, carboxamide 1H), 3.52-3.48 (m, 1H), 3.17-3.13 (m, 4H), 3.09-3.06 (m, 1H), 2.99-2.95 (m, 1H), 2.82-2.68 (m, 4H), 2.59 (s, 3H), 2.03-2.00 (m, 1H), 1.92-1.84 (m, 1H),1.61 (br s, 2H),1.25 (s, 3H) 428 3-amino-N-[(6S)-2-[(3S,4R)-4- 467 (DMSO-d6, 400 MHz) δ(ppm): 8.31 (d, J = +++ amino-3-methoxy-3- 8.0 Hz, 1H),7.58 (br s, 1H), 7.31 (d, J = methylpyrrolidin-1-yl]-5,6,7,8- 8.4 Hz, 1H), 7.18 (d, J = 8.4 Hz, tetrahydroquinolin-6-yl]-6- 1H),7.16 (br s, 2H), 6.21 (d, J = 8.4 Hz, methylthieno[2,3-b]pyridine-2- 1H), 4.17-4.10 (m, 1H), 3.80-3.77 (m, carboxamide 1H), 3.53-3.49 (m, 1H), 3.18-3.14 (m, 4H), 3.08-3.05 (m, 1H), 2.98-2.93 (m, 1H), 2.82-2.68 (m, 4H), 2.59 (s, 3H), 2.03-2.00 (m, 1H), 1.92-1.84 (m, 1H),1.61 (br s, 2H),1.25 (s, 3H) 429 3-amino-N-[(6S)-2-{7-amino- 527 (DMSO-d6, 400 MHz) δ(ppm): 8.31 (d, J = ++++ 3,3-dioxo-3λ⁶-thia-9- 8.4 Hz, 1H),7.62 (br s, 1H), 7.36-7.30 azabicyclo[3.3.1]nonan-9-yl]- (m, 2H), 7.17 (br s, 2H), 6.82 (d, J = 8.0 5,6,7,8-tetrahydroquinolin-6-yl]- Hz, 1H), 5.31-5.25 (m, 2H), 4.19-4.12 6-methylthieno[2,3-b]pyridine-2- (m, 1H),3.24-3.21 (m, 3H), 3.11-3.06 (m, carboxamide 2H), 2.88-2.63 (m, 6H), 2.59 (s, 3H), 2.27-2.18 (m, 2H), 2.05-1.99 (m, 1H), 1.93-1.86 (m, 3H) 430 3-amino-N-[(6S)-2-[(5S,9R)-9- 479 (DMSO-d6, 400 MHz) δ(ppm): 8.30 (d, J = +++ amino-2-oxa-7- 8.0 Hz, 1H),7.56 (br s, 1H), 7.31 (d, J = azaspiro[4.4]nonan-7-yl]- 8.0 Hz, 1H), 7.18 (d, J = 8.4 Hz, 5,6,7,8-tetrahydroquinolin-6-yl]- 1H),7.15 (br s, 2H), 6.21 (d, J = 8.4 Hz, 6-methylthieno[2,3-b]pyridine-2- 1H), 4.16-4.10 (m, 1H), 3.81-3.75 (m, carboxamide 2H), 3.56-3.45 (m, 4H),3.34-3.23 (m, 2H), 3.10-3.07 (m, 1H), 2.80-2.71 (m, 4H), 2.58 (s, 3H), 2.18-2.14 (m, 1H), 2.03-1.96 (m, 1H), 1.86-1.78 (m, 1H), 1.72 (br s, 2H), 1.58-1.54 (m, 1H) 431 3-amino-N-[(6S)-2-[(5R,9S)-9- 479 (DMSO-d6, 400 MHz) δ(ppm): 8.30 (d, J = +++ amino-2-oxa-7- 8.0 Hz, 1H),7.56 (br s, 1H), 7.31 (d, J = azaspiro[4.4]nonan-7-yl]- 8.0 Hz, 1H), 7.18 (d, J = 8.4 Hz, 5,6,7,8-tetrahydroquinolin-6-yl]- 1H),7.15 (br s, 2H), 6.21 (d, J = 8.4 Hz, 6-methylthieno[2,3-b]pyridine-2- 1H), 4.1-4.10 (m, 1H), 3.81-3.75 (m, carboxamide 2H), 3.56-3.45 (m, 4H),3.34-3.23 (m, 2H), 3.10-3.07 (m, 1H), 2.80-2.71 (m, 4H), 2.58 (s, 3H), 2.18-2.14 (m, 1H), 2.03-1.96 (m, 1H), 1.87-1.80 (m, 1H), 1.71 (br s, 2H), 1.61-1.57 (m, 1H) 432 3-amino-N-[(3R)-7-[(5S,9S)-9- 480 (DMSO-d6, 400 MHz) δ(ppm): 8.33 (d, J = ++++ amino-2-oxa-7- 8.0 Hz, 1H),7.49 (br s, 1H), 7.32 (d, J = azaspiro[4.4]nonan-7-yl]-3,4- 8.4 Hz, 1H), 7.22 (br s, 2H), 6.88 (d, J = dihydro-2H-1-benzopyran-3-yl]- 8.4 Hz, 1H), 6.10 (dd, J = 8.4, 2.0 Hz, 6-methylthieno[2,3-b]pyridine-2- 1H), 5.91 (s, 1H), 4.32-4.26 (m, 1H), carboxamide 4.16-4.13 (m, 1H), 3.81-3.77 (m, 3H), 3.58 (d, J = 8.4 Hz, 1H), 3.48 (d, J = 8.4 Hz, 1H), 3.43-3.40 (m, 1H), 3.34-3.30 (m, 2H), 3.17-3.15 (m, 1H), 3.03-3.01 (m, 1H), 2.89-2.81 (m, 2H), 2.59 (m, 3H), 2.21-2.17 (m, 1H), 1.68-1.61 (m, 1H) 433 3-amino-N-[(3R)-7-[(5R,9S)-9- 480 (DMSO-d6, 400 MHz) δ(ppm): 8.33 (d, J = ++++ amino-2-oxa-7- 8.0 Hz, 1H),7.50 (br s, 1H), 7.32 (d, J = azaspiro[4.4]nonan-7-yl]-3,4- 8.4 Hz, 1H), 7.22 (br s, 2H), 6.87 (d, J = dihydro-2H-1-benzopyran-3-yl]- 8.0 Hz, 1H), 6.09 (d, J = 8.4 Hz, 1H), 6-methylthieno[2,3-b]pyridine-2- 5.89 (s, 1H), 4.31-4.27 (m, 1H), 4.15- carboxamide 4.12 (m, 1H), 3.93 (d, J = 8.8 Hz,1H), 3.81-3.73 (m, 3H), 3.44-3.40 (m, 2H), 3.34-3.25 (m, 2H), 3.12-3.10 (m, 1H), 2.92-2.81 (m, 1H), 2.85-2.78 (m, 2H), 2.59 (s, 3H), 1.88-1.83 (m, 1H), 1.74- 1.68 (m, 3H) 434 N-[(6S)-2-[(3aR,6aS)-3a- 479 (DMSO-d6 400 MHz) δ(ppm): 8.30 (d, J = +++ methoxy-octahydropyrrolo[2,3- 8.4 Hz, 1H),7.57 (br s, 1H), 7.31 (d, J = c]pyrrol-5-yl]-5,6,7,8- 8.0 Hz, 1H),7.21 (d, J = 8.4 Hz, 1H) tetrahydroquinolin-6-yl]-3- 7.15 (br s, 2H), 6.31 (d, J = 8.4 Hz, 1H), amino-6-methylthieno[2,3- 4.14-4.08 (m, 1H), 3.65-3.53 (m, 3H), b]pyridine-2-carboxamide 3.46-3.43 (m, 1H), 3.27-3.18 (m, 5H), 2.99-2.91 (m, 2H), 2.82-2.69(m, 4H), 2.58 (s, 3H), 2.04-1.99 (m, 2H), 1.90- 1.82 (m, 2H) 435 N-[(6S)-2-[(3aS,6aR-3a- 479 (DMSO-d6 400 MHz) δ(ppm): 8.29 (d, J = +++ methoxy-octahydropyrrolo[2,3- 8.4 Hz, 1H),7.57 (br s, 1H), 7.31 (d, J = c]pyrrol-5-yl]-5,6,7,8- 8.0 Hz, 1H),7.21 (d, J = 8.4 Hz, 1H) tetrahydroquinolin-6-yl]-3- 7.15 (br s, 2H), 6.31 (d, J = 8.4 Hz, 1H), amino-6-methylthieno[2,3- 4.14-4.08 (m, 1H), 3.65-3.53 (m, 3H), b]pyridine-2-carboxamide 3.46-3.43 (m, 1H), 3.27-3.18 (m, 5H), 2.99-2.91 (m, 2H), 2.82-2.69(m, 4H), 2.58 (s, 3H), 2.04-1.99 (m, 2H), 1.90- 1.82 (m, 2H) 436 3-amino-N-[(2S)-6-[(3R,4R)-3- 454 (MeOH-d4, 400 MHz) δ(ppm): 8.21 (d, J = ++++ amino-4- 8.0 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), (fluoromethyl)pyrrolidin-1-yl]- 6.43 (dd, J = 8.4, 2.4 Hz, 1H), 6.35 (s, 1,2,3,4-tetrahydronaphthalen-2- 1H), 4.81-4.61 (m, 3H), 4.26-4.21 (m, yl]-6-methylthieno[2,3- 1H), 3.81-3.79 (m, 1H), 3.57-3.53 (m, b]pyridine-2-carboxamide 3H), 3.45-3.41 (m, 1H), 3.24-3.21 (m, 1H), 3.01-2.89 (m, 3H), 2.79-2.73 (m, 2H), 2.66 (s, 3H), 2.14-2.11 (m, 1H), 1.89-1.81 (m, 1H) 437 3-amino-N-[(6S)-2-[(5R,9R)-9- 479 (DMSO-d6, 400 MHz) δ(ppm): 8.31 (d, J = amino-2-oxa-7- 8.4 Hz, 1H),7.58 (br s, 1H), 7.31 (d, J = azaspiro[4.4]nonan-7-yl]- 8.0 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 5,6,7,8-tetrahydroquinolin-6-yl]- 7.17 (br s, 2H), 6.22 (d, J = 8.8 Hz, 1H), 6-methylthieno[2,3-b]pyridine-2- 4.15-4.10 (m, 1H), 3.93 (d, J = 8.8 Hz, carboxamide 1H), 3.83-3.75 (m, 2H), 3.54-3.51 (m, 1H), 3.49-3.42 (m, 2H), 3.34-3.26 (m, 2H), 3.12-3.10 (m, 1H), 2.81-2.70 (m, 4H), 2.59 (s, 3H), 2.03-1.98 (m, 1H), 1.89-1.82 (m, 2H), 1.76-1.68 (m, 3H) 438 3-amino-N-[(6S)-2-[(5S,9S)-9- 479 (DMSO-d6, 400 MHz) δ(ppm): 8.31 (d, J = amino-2-oxa-7- 8.4 Hz, 1H),7.58 (br s, 1H), 7.31 (d, J = azaspiro[4.4]nonan-7-yl]- 8.4 Hz, 1H), 7.19 (d, J = 8.8 Hz, 1H), 5,6,7,8-tetrahydroquinolin-6-yl]- 7.16 (br s, 2H), 6.22 (d, J = 8.4 Hz, 1H), 6-methylthieno[2,3-b]pyridine-2- 4.15-4.10 (m, 1H), 3.93 (d, J = 8.8 Hz, carboxamide 1H), 3.81-3.73 (m, 2H), 3.58-3.55 (m, 1H), 3.53-3.50 (m, 1H),3.48-3.41 (m, 1H), 3.30-3.27 (m, 2H), 3.12-3.10 (m, 1H), 2.81-2.70 (m, 4H), 2.59 (s, 3H), 2.03-1.98 (m, 1H), 1.89-1.82 (m, 2H), 1.76-1.68 (m, 3H) 439 3-amino-N-[(3R)-7-[(5R,9R)-9- 480 (DMSO-d6, 400 MHz) δ(ppm): 8.32 (d, J = amino-2-oxa-7- 8.4 Hz, 1H),7.48 (br s, 1H), 7.31 (d, J = azaspiro[4.4]nonan-741-3,4- 8.4 Hz, 1H), 7.21 (br s, 2H), 6.86 (d, J = dihydro-2H-1-benzopyran-3-yl]- 8.4 Hz, 1H), 6.08 (d, J = 6.8 Hz, 1H), 6-methylthieno[2,3-b]pyridine-2- 5.88 (s, 1H), 4.27-4.24 (m, 1H), 4.15- carboxamide 4.12 (m, 1H), 3.81-3.77 (m, 3H), 3.55 (d, J = 8.4 Hz, 1H), 3.48 (d, J = 8.4 Hz, 1H),3.39-3.36 (m, 1H), 3.32-3.23 (m, 2H), 3.14-3.11 (m, 1H), 2.92-2.90 (m, 1H), 2.89-2.81 (m, 2H), 2.58 (s, 3H), 2.10-2.06 (m, 1H), 1.72 (br s, 2H), 1.61- 1.57 (m, 1H) 440 3-amino-N-[(3R)-7-[(5S,9R)-9- 480 (DMSO-d6, 400 MHz) δ(ppm): 8.33 (d, J = amino-2-oxa-7- 8.4 Hz, 1H),7.49 (br s, 1H), 7.32 (d, J = azaspiro[4.4]nonan-7-yl]-3,4- 8.4 Hz, 1H), 7.21 (br s, 2H), 6.87 (d, J = dihydro-2H-1-benzopyran-3-yl ]- 8.4 Hz, 1H), 6.09 (d, J = 6.8 Hz, 1H), 6-methylthieno[2,3-b]pyridine-2- 5.89 (s, 1H), 4.28-4.24 (m, 1H), 4.16- carboxamide 4.13 (m, 1H), 3.93 (d, J = 8.8 Hz,1H), 3.82-3.71 (m, 3H), 3.44-3.40 (m, 2H),3.33-3.27 (m, 2H), 3.12-3.10 (m, 1H), 2.93-2.89 (m, 1H), 2.85-2.78 (m, 2H), 2.59 (s, 3H), 1.91-1.85 (m, 3H), 1.74-1.71 (m, 1H) 441 3-amino-N-[(6S)-2-[(3R,4R)-3- 469 (DMSO-d6, 400 MHz) δ(ppm): 8.31 (d, J = (fluoromethyl)-4- 8.0 Hz, 1H),7.57 (br s, 1H), 7.31 (d, J = (methylamino)pyrrolidin-1-yl]- 8.0 Hz, 1H),7.20 (d, J = 8.4 Hz, 1H) 5,6,7,8-tetrahydroquinolin-6-yl]- 7.17 (br s, 2H), 6.26 (d, J = 8.8 Hz, 1H), 6-methylthieno[2,3-b]pyridine-2- 4.76-4.61 (m, 1H), 4.53-4.37 (m, 1H), carboxamide 4.15-4.11 (m, 1H), 3.53-3.51 (m, 1H), 3.44-3.42 (m, 2H), 3.23-3.20 (m, 1H), 2.82-2.68 (m, 6H), 2.59 (s, 3H), 2.31 (s, 3H), 2.04-1.98 (m, 1H), 1.88-1.82 (m, 2H) 442 3-amino-N-[(6S)-2-[(3S,4S)-3- 469 (DMSO-d6, 400 MHz) δ(ppm): 8.30 (d, J = (fluoromethyl)-4- 8.0 Hz, 1H),7.58 (br s, 1H), 7.31 (d, J = (methylamino)pyrrolidin-1-yl]- 8.4 Hz, 1H),7.20 (d, J = 8.4 Hz, 1H) 5,6,7,8-tetrahydroquinolin-6-yl]- 7.16 (br s, 2H), 6.26 (d, J = 8.4 Hz, 1H), 6-methylthieno[2,3-b]pyridine-2- 4.76-4.61 (m, 1H), 4.53-4.37 (m, 1H), carboxamide 4.15-4.11 (m, 1H), 3.51-3.48 (m, 2H), 3.38-3.21 (m, 2H), 2.82-2.75 (m, 6H), 2.59 (s, 3H), 2.31 (s, 3H), 2.04-1.98 (m, 1H), 1.90-1.82 (m, 2H) 443 3-amino-N-[(3R)-7-[(3R,4R)-3- 470 (DMSO-d6, 400 MHz) δ(ppm): 8.32 (d, J = (fluoromethyl)-4- 8.0 Hz, 1H),7.51 (br s, 1H), 7.32 (d, J = (methylamino)pyrrolidin-1-yl]- 8.4 Hz, 1H), 7.21 (br s, 2H), 6.88 (d, J = 3,4-dihydro-2H-1-benzopyran-3- 8.4 Hz, 1H), 6.12 (d, J = 7.6 Hz, 1H), yl]-6-methylthieno[2,3- 5.93 (s, 1H), 4.78-4.60 (m, 1H), 4.52- b]pyridine-2-carboxamide 4.36 (m, 1H), 4.32-4.25 (m, 1H), 4.15- 4.13 (m, 1H), 3.82-3.77 (m, 1H), 3.40- 3.37 (m, 3H), 3.23-3.21 (m, 1H), 3.08- 3.06 (m, 1H), 2.87-2.83 (m, 2H), 2.78- 2.69 (m, 1H), 2.59 (s, 3H), 2.30 (s, 3H), 1.91-1.84 (m, 1H), 1.83 (br s, 1H) 444 3-amino-N-[(3R)-7-[(3S,4S)-3- 470 (DMSO-d6 400 MHz) δ(ppm): 8.33 (d, J = (fluoromethyl)-4- 8.0 Hz, 1H),7.50 (br s, 1H), 7.32 (d, J = (methylamino)pyrrolidin-1-yl]- 8.4 Hz, 1H), 7.22 (br s, 2H), 6.88 (d, J = 3,4-dihydro-2H-1-benzopyran-3- 8.4 Hz, 1H), 6.12 (dd, J = 8.4,2.4 Hz, yl]-6-methylthieno[2,3- 1H), 5.93 (s, 1H), 4.75-4.61 (m, 1H), b]pyridine-2-carboxamide 4.51-4.36 (m, 1H), 4.32-4.25 (m, 1H), 4.15-4.13 (m, 1H), 3.82-3.77 (m, 1H), 3.40-3.37 (m, 3H), 3.23-3.21 (m, 1H), 3.08-3.06 (m, 1H), 2.87-2.83 (m, 2H), 2.78-2.69 (m, 1H), 2.59 (s, 3H), 2.30 (s, 3H), 1.91-1.84 (m, 1H), 1.82 (br s, 1H) 445 3-amino-N-[(6R)-2-[(3R,4R)- 3- 456 (DMSO-d6 400 MHz) δ(ppm): 8.31 (d, J = amino-4- 8.4 Hz, 1H), 8.07 (s, 1H), 7.63 (br s, (fluoromethyl)pyrrolidin-1-yl]- 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.17 (br s, 5,6,7,8-tetrahydroquinazolin-6- 2H), 4.80-4.47 (m, 2H), 4.14-4.08 (m, yl]-6-methylthieno[2,3- 1H), 3.61-3.57 (m, 5H), 2.84-2.64 (m, b]pyridine-2-carboxamide 4H), 2.60-2.57 (m, 4H), 2.04-1.98 (m, 1H), 1.91-1.84 (m, 1H), 1.72 (br s, 2H) 446 3-amino-N-[(6R)-2-[(3S,4S)-3- 456 (DMSO-d6, 400 MHz) δ(ppm): 8.31 (d, J = amino-4- 8.0 Hz, 1H), 8.07 (s, 1H), 7.63 (br s, (fluoromethyl)pyrrolidin-1-yl]- 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.17 (br s, 5,6,7,8-tetrahydroquinazolin-6- 2H), 4.80-4.47 (m, 2H), 4.12-4.10 (m, yl]-6-methylthieno[2,3- 1H), 3.61-3.57 (m, 5H), 2.84-2.64 (m, b]pyridine-2-carboxamide 4H), 2.60-2.57 (m, 4H), 2.04-1.98 (m, 1H), 1.91-1.84 (m, 1H), 1.75 (br s, 2H) 447 3-amino-N-[(2S)-6-[(3S,4S)-3- 454 (DMSO-d6, 400 MHz) δ(ppm): 8.30 (d, J = amino-4- 8.4 Hz, 1H), 7.54 (br s, 1H), 7.31 (d, J = (fluoromethyl)pyrrolidin-1-yl]- 8.0 Hz, 1H), 7.15 (br s, 2H), 6.89 (d, J = 1,2,3,4-tetrahydronaphthalen-2- 8.4 Hz, 1H), 6.34(d, J = 8.8 Hz, 1H), yl]-6-methylthieno[2,3- 6.25 (s, 1H), 4.80-4.52 (m, 2H), 4.13- b]pyridine-2-carboxamide 4.07 (m, 1H), 3.77-3.74 (m, 1H), 3.27- 3.22 (m, 3H), 3.14-3.12 (m, 1H), 2.86- 2.68 (m, 6H), 2.59-2.57 (m, 4H), 1.99- 1.93 (m, 1H), 1.82-1.71 (m, 1H) 448 N-((2S)-6-(9-oxa-3,7- 465 Library format synthesis, 1H NMR not ++++ ++ ++ diazabicyclo[3.3.1]nonan-3-yl)- taken. 1,2,3,4-tetrahydronaphthalen-2- yl)-7-amino-3-methylthieno[2,3- b]pyrazine-6-carboxamide 449 N-((2S)-6-(9-oxa-3,7- 464 Library format synthesis, 1H NMR not ++ diazabicyclo[3.3.1]nonan-3-yl)- taken. 1,2,3,4-tetrahydronaphthalen-2- yl)-3-amino-6-methylthieno[2,3- b]pyridine-2-carboxamide 450 N-((2R)-6-(9-oxa-3,7- 465 Library format synthesis, 1H NMR not ++ + + diazabicyclo[3.3.1]nonan-3-yl)- taken. 1,2,3,4-tetrahydronaphthalen-2- yl)-7-amino-3-methylthieno[2,3- b]pyrazine-6-carboxamide 451 N-((2R)-6-(9-oxa-3,7- 464 Library format synthesis, 1H NMR not +++ ++ ++ diazabicyclo[3.3.1]nonan-3-yl)- taken. 1,2,3,4-tetrahydronaphthalen-2- yl)-3-amino-6-methylthieno[2,3- b]pyridine-2-carboxamide 452 (R)-N-(6-(1,4-diazepan-1-yl)- 437 Library format synthesis, 1H NMR not ++ + + 1,2,3,4-tetrahydronaphthalen-2- taken. yl)-7-amino-3-methylthieno[2,3- b]pyrazine-6-carboxamide 453 7-amino-N-((R)-6-((S)-6-fluoro- 455 Library format synthesis, 1H NMR not +++ ++ ++ 1,4-diazepan-1-yl)-1,2,3,4- taken. tetrahydronaphthalen-2-yl)-3- methylthieno[2,3-b]pyrazine-6- carboxamide 454 (S)-7-amino-N-(6-(6,6-difluoro- 473 Library format synthesis, 1H NMR not +++ 1,4-diazepan-1-yl)-1,2,3,4- taken. tetrahydronaphthalen-2-yl)-3- methylthieno[2,3-b]pyrazine-6- carboxamide 455 (S)-N-(6-(1,4-diazepan-1-yl)- 437 Library format synthesis, 1H NMR not +++ ++ ++ 1,2,3,4-tetrahydronaphthalen-2- taken. yl)-7-amino-3-methylthieno[2,3- b]pyrazine-6-carboxamide 456 N-((2S)-6-(3-oxa-7,9- 465 Library format synthesis, 1H NMR not +++ ++ + diazabicyclo[3.3.1]nonan-7-yl)- taken. 1,2,3,4-tetrahydronaphthalen-2- yl)-7-amino-3-methylthieno[2,3- b]pyrazine-6-carboxamide 457 (R)-7-bromo-N-(7-(piperazin-1- 457 Library format synthesis, 1H NMR not ++ yl)chroman-3-yl)pyrazolo[1,5- taken. a]pyridine-3-carboxamide 458 (R)-7-methyl-N-(7-(piperazin-1- 392 Library format synthesis, 1H NMR not ++++ ++ yl)chroman-3-yl)pyrazolo[1,5- taken. a]pyridine-3-carboxamide 459 (R)-1-acetyl-N-(7-(piperazin-1- 435 Library format synthesis, 1H NMR not + + + yl)chroman-3-yl)-1,2,3,4- taken. tetrahydroquinoline-6- carboxamide 460 (R)-N-(7-(piperazin-1- 378 Library format synthesis, 1H NMR not + + + yl)chroman-3-yl)pyrazolo[1,5- taken. a]pyridine-3-carboxamide 461 (R)-5-methoxy-N-(7-(piperazin- 408 Library format synthesis, 1H NMR not + + 1-yl)chroman-3-yl)pyrazolo[1,5- taken. a]pyridine-3-carboxamide 462 (R)-6-chloro-N-(7-(piperazin-1- 412 Library format synthesis, 1H NMR not + + + yl)chroman-3-yl)pyrazolo[1,5- taken. a]pyridine-3-carboxamide 407 463 (R)-5,7-dimethyl-N-(7- Library format synthesis, 1H NMR not + + + (piperazin-1-yl)chroman-3- taken. yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 464 (R)-6-chloro-N-(7-(piperazin-1- 413 Library format synthesis, 1H NMR not + + yl)chroman-3-yl)imidazo[1,2- taken. b]pyridazine-2-carboxamide 465 (R)-5-methyl-N-(7-(piperazin-1- 392 Library format synthesis, 1H NMR not + + yl)chroman-3-yl)pyrazolo[1,5- taken. a]pyridine-3-carboxamide 466 (R)-N-(7-(piperazin-1- 379 Library format synthesis, 1H NMR not + + yl)chroman-3-yl)pyrazolo[1,5- taken. a]pyrimidine-3-carboxamide 467 (R)-6-((3-chlorobenzyl)amino)- 477 Library format synthesis, 1H NMR not ++ ++ N-(7-(piperazin-1-yl)chroman-3- taken. yl)nicotinamide 468 (R)-N-(7-(piperazin-1- 445 Library format synthesis, 1H NMR not ++ + + yl)chroman-3-yl)-6-((pyridin-3- taken. ylmethyl)amino)nicotinamide 469 (R)-N-(7-(piperazin-1- 512 Library format synthesis, 1H NMR not +++ ++ +++ yl)chroman-3-yl)-6-((3- taken. (trifluoromethyl)benzyl) amino)nicotinamide 470 (R)-N-(7-(piperazin-1- 445 Library format synthesis, 1H NMR not + + + yl)chroman-3-yl)-6-((pyridin-2- taken. ylmethyl)amino)nicotinamide 471 (R)-6-(((2,3- 502 Library format synthesis, 1H NMR not ++ + ++ dihydrobenzo[b][1,4]dioxin-6- taken. yl)methyl)amino)-N-(7- (piperazin-1-yl)chroman-3- yl)nicotinamide 472 (R)-6-(((2,3-dihydrobenzofuran- 486 Library format synthesis, 1H NMR not ++ ++ ++ 5-yl)methyl)amino)-N-(7- taken. (piperazin-1-yl)chroman-3- yl)nicotinamide 473 (R)-6-((3- 501 Library format synthesis, 1H NMR not + + + acetamidobenzyl)amino)-N-(7- taken. (piperazin-1-yl)chroman-3- yl)nicotinamide 474 7-ethyl-N-[(3R)-7-(piperazin-1- 406 Library format synthesis, 1H NMR not ++++ ++ yl)-3,4-dihydro-2H-1- taken. benzopyran-3-yl]pyrazolo[1,5- a]pyridine-3-carboxamide 475 7-(hydroxymethyl)-N-[(3R)-7- 408 Library format synthesis, 1H NMR not ++ + (piperazin-1-yl)-3,4-dihydro-2H- taken. 1-benzopyran-3-yl]pyrazolo[1,5- a]pyridine-3-carboxamide

TABLE 25

36. (R)-7-amino-2-ethyl-N-(7-(piperazin-1- yl)chroman-3-yl)thieno[2,3-b]pyrazine-6- carboxamide

37. (S)-7-amino-2-ethyl-N-(7-(piperazin-1- yl)chroman-3-yl)thieno[2,3-b]pyrazine-6- carboxamide

38. (R)-1-(difluoromethyl)-N-(7-(piperazin-1- yl)chroman-3-yl)-1H-pyrrolo[2,3-b]pyridine- 5-carboxamide

39. (S)-1-(difluoromethyl)-N-(7-(piperazin-1- yl)chroman-3-yl)-1H-pyrrolo[2,3-b]pyridine- 5-carboxamide

40. N-((3R)-7-(3,8-diazabicyclo[3.2.1]octan- 3-yl)-6-fluorochroman-3-yl)-7-amino-3- methylthieno[2,3-b]pyrazine-6-carboxamide

41. N-((3S)-7-(3,8-diazabicyclo[3.2.1]octan- 3-yl)-6-fluorochroman-3-yl)-7-amino-3- methylthieno[2,3-b]pyrazine-6-carboxamide

42. 3-amino-N-((S)-7-((3aS,6aS)- hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)chroman-3-yl)-6-methylthieno[2,3- b]pyridine-2-carboxamide

43. 3-amino-N-((R)-7-((3aR,6aR)- hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)chroman-3-yl)-6-methylthieno[2,3- b]pyridine-2-carboxamide

44. 3-amino-N-((S)-7-((3aR,6aR)- hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)chroman-3-yl)-6-methylthieno[2,3- b]pyridine-2-carboxamide

45. (R)-6-amino-2-cyclopropyl-N-(7- (piperazin-1-yl)chroman-3-yl)thieno[2,3- d]thiazole-5-carboxamide

46. N-((3S)-7-(3,8-diazabicyclo[3.2.1]octan- 3-yl)-6-fluorochroman-3-yl)-6-amino-2- methylthieno[2,3-d]thiazole-5-carboxamide

47. N-((3R)-7-(3,8-diazabicyclo[3.2.1]octan- 3-yl)-6-fluorochroman-3-yl)-6-amino-2- methylthieno[2,3-cl]thiazole-5-carboxamide

48. (R)-3-amino-N-(5-chloro-7-(piperazin-1- yl)chroman-3-yl)-6-methylthieno[2,3- b]pyridine-2-carboxamide

49. (S)-3-amino-N-(5-chloro-7-(piperazin-1- yl)chroman-3-yl)-6-methylthieno[2,3- b]pyridine-2-carboxamide

50. N-((3R)-7-(3,8-diazabicyclo[3.2.1]octan- 3-yl)chroman-3-yl)-5,6,7,8-tetrahydro-1,8- naphthyridine-3-carboxamide

51. N-((3R)-7-(3,8-diazabicyclo[3.2.1]octan- 3-yl)chroman-3-yl)-3,4-dihydro-2H- pyrano[2,3-b]pyridine-6-carboxamide

52. (R)-6-(benzylamino)-N-(7-(piperazin-1- yl)chroman-3-yl)nicotinamide

53. 6-(((S)-1-phenylethyl)amino)-N-((R)-7- (piperazin-1-yl)chroman-3-yl)nicotinamide

54. 6-(((R)-1-phenylethyl)amino)-N-((R)-7- (piperazin-1-yl)chroman-3-yl)nicotinamide

55. (R)-3-amino-N-(5,8-difluoro-7- (piperazin-1-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide

56. (R)-6-amino-N-(5,8-difluoro-7- (piperazin-1-yl)chroman-3-yl)-2- methylthieno[2,3-d]thiazole-5-carboxamide

57. (R)-7-hydroxy-N-((R)-7-(piperazin-1- yl)chroman-3-yl)-6,7-dihydro-5H- cyclopenta[b]pyridine-3-carboxamide

58. (S)-7-hydroxy-N-((R)-7-(piperazin-1- yl)chroman-3-yl)-6,7-dihydro-5H- cyclopenta[b]pyridine-3-carboxamide

59. (R)-1-benzyl-N-(7-(piperazin-1- yl)chroman-3-yl)-1H-pyrrolo[2,3-b]pyridine- 5-carboxamide

60. (R)-7-amino-N-(8-cyano-5-fluoro-7- (piperazin-1-yl)chroman-3-yl)-3- methylthieno[2,3-b]pyrazine-6-carboxamide

61. (R)-3-amino-N-(5,6-difluoro-7- (piperazin-1-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide

62. 3-amino-N-((R)-7-((3S,4R)-3- hydroxypiperidin-4-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide

63. 3-amino-N-((R)-7-((3R,4S)-3- hydroxypiperidin-4-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide

64. 3-amino-N-((R)-7-((3R,4R)-3- hydroxypiperidin-4-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide

65. 3-amino-N-((R)-7-((3S,4S)-3- hydroxypiperidin-4-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide

66. (R)-6-amino-N-(5,6-difluoro-7- (piperazin-1-yl)chroman-3-yl)-2- methylthieno[2,3-d]thiazole-5-carboxamide

67. (R)-7-amino-N-(6-cyano-5-fluoro-7- (piperazin-1-yl)chroman-3-yl)-3- methylthieno[2,3-b]pyrazine-6-carboxamide

68. (R)-3-amino-N-(5,8-difluoro-7- (piperazin-1-yl)chroman-3-yl)-6- methylfuro[2,3-b]pyridine-2-carboxamide

69. 3-amino-N-((R)-7-((R)-3,3- difluoropiperidin-4-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide

70. 3-amino-N-((R)-7-((S)-3,3- difluoropiperidin-4-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide

71. (R)-7-amino-3-methyl-N-(7-(piperazin-1- yl)-3,4-dihydro-2H-pyrano[3,2-c]pyridin-3- yl)thieno[2,3-b]pyrazine-6-carboxamide

72. (R)-3-amino-5-fluoro-6-methyl-N-(7- (piperazin-1-yl)-3,4-dihydro-2H-pyrano[3,2- c]pyridin-3-yl)thieno[2,3-b]pyridine-2- carboxamide

73. (7S)-N-((3R)-7-(3,8- diazabicyclo[3.2.1]octan-3-yl)chroman-3-yl)- 7-methyl-5,6,7,8-tetrahydro-1,8- naphthyridine-3-carboxamide

74. (7R)-N-((3R)-7-(3,8- diazabicyclo[3.2.1]octan-3-yl)chroman-3-yl)- 7-methyl-5,6,7,8-tetrahydro-1,8- naphthyridine-3-carboxamide

75. N-((R)-7-((1S,4S)-2,5- diazabicyclo[2.2.2]octan-2-yl)-3,4-dihydro- 2H-pyrano[3,2-c]pyridin-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

76. N-((R)-7-((1R,4R)-2,5- diazabicyclo[2.2.2]octan-2-yl)-3,4-dihydro- 2H-pyrano[3,2-c]pyridin-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

77. N-((3R)-7-(3,6- diazabicyclo[3.1.1]heptan-3-yl)-8-cyano-5- fluorochroman-3-yl)-7-amino-3- methylthieno[2,3-b]pyrazine-6-carboxamide

78. N-((3R)-7-(9-oxa-3,7- diazabicyclo[3.3.1]nonan-3-yl)-5,8- difluorochroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

79. N-((3R)-7-(9-oxa-3,7- diazabicyclo[3.3.1]nonan-3-yl)-5,6- difluorochroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

80. 3-amino-N-((R)-7-((3R,4R)-3- fluoropiperidin-4-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide

81. 3-amino-N-((R)-7-((3S,4S)-3- fluoropipendin-4-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide

82. 3-amino-N-((R)-7-((3S,4R)-3- fluoropiperidin-4-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide

83. 3-amino-N-((R)-7-((3R,4S)-3- fluoropiperidin-4-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide

84. N-((R)-5,8-difluoro-7-((3R,4S)-3- hydroxypiperidin-4-yl)chroman-3-yl)-7-ethyl- 7H-pyrrolo[2,3-c]pyridazine-3-carboxamide

85. N-((R)-5,8-difluoro-7-((3S,4R)-3- hydroxypiperidin-4-yl)chroman-3-yl)-7-ethyl- 7H-pyrrolo[2,3-c]pyridazine-3-carboxamide

86. 3-amino-N-((R)-7-((3R,4R)-3-amino-4- methoxypyrrolidin-1-yl)-5,8- difluorochroman-3-yl)-6-methylthieno[2,3- b]pyridine-2-carboxamide

87. 3-amino-N-((R)-7-((3S,4S)-3-amino-4- methoxypyrrolidin-1-yl)-5,8- difluorochroman-3-yl)-6-methylthieno[2,3- b]pyridine-2-carboxamide

88. N-((3R)-7-(9-oxa-3,7- diazabicyclo[3.3.1]nonan-3-yl)chroman-3- yl)-3-amino-4-(difluoromethyl)-6- methylthieno[2,3-b]pyridine-2-carboxamide

89. (1aS,7bR)-N-((3R)-7-(3,8- diazabicyclo[3.2.1]octan-3-yl)-5,8- difluorochroman-3-yl)-1a,2,3,7b-tetrahydro- 1H-cyclopropa[c][1,8]naphthyridine-6- carboxamide

90. (1aR,7bS)-N-((3R)-7-(3,8- diazabicyclo[3.2.1]octan-3-yl)-5,8- difluorochroman-3-yl)-1a,2,3,7b-tetrahydro- 1H-cyclopropa[c][1,8]naphthyridine-6- carboxamide

91. 3-amino-N-[(3R)-7-[(3R,4R)-3-amino-4- methoxypyrrolidin-1-yl]-8-fluoro-3,4-dihydro- 2H-1-benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

92. 3-amino-N-[(3R)-7-[(3S,4S)-3-amino-4- methoxpyrrolidin-1-yl]-8-fluoro-3,4-dihydro- 2H-1-benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

93. 3-amino-N-[(3R)-7-[(3R,4R)-3-amino-4- methoxypyrrolidin-1-yl]-6-fluoro-3,4-dihydro- 2H-1-benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

94. 3-amino-N-[(3R)-7-[(3S,4S)-3-amino-4- methoxypyrrolidin-1-yl]-6-fluoro-3,4-dihydro- 2H-1-benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

95. 3-amino-N-[(3R)-8-cyano-7-{3,8- diazabicyclo[3.2.1]octan-3-yl}-5-fluoro-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

96. 3-amino-N-[(3R)-8-cyano-5-fluoro-7-{9- oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl}-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

97. 7-amino-N-[(3R)-7-{3,8- diazabicyclo[3.2.1]octan-3-yl}-5,6-difluoro- 3,4-dihydro-2H-1-benzopyran-3-yl]-3- methylthieno[2,3-b]pyrazine-6-carboxamide

98. 6-amino-N-[(3R)-7-{3,8- diazabicyclo[3.2.1]octan-3-yl}-5,8-difluoro- 3,4-dihydro-2H-1-benzopyran-3-yl]-2- methylthieno[2,3-d][1,3]thiazole-5- carboxamide

99. 3-amino-N-[(2S)-5-fluoro-6-{9-oxa-3,7- diazabicyclo[3.3.1]nonan-3-yl}-1,2,3,4- tetrahydronaphthalen-2-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

100. 3-amino-N-[(2R)-5-fluoro-6-{9-oxa-3,7- diazabicyclo[3.3.1]nonan-3-yl}-1,2,3,4- tetrahydronaphthalen-2-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

101. 3-amino-N-[(2S)-7-fluoro-6-{9-oxa-3,7- diazabicyclo[3.3.1]nonan-3-yl}-1,2,3,4- tetrahydronaphthalen-2-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

102. 3-amino-N-[(2S)-5-cyano-6-{9-oxa-3,7- diazabicyclo[3.3.1]nonan-3-yl}-1,2,3,4- tetrahydronaphthalen-2-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

103. 3-amino-N-[(3R)-7-{3,8- diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

104. 3-amino-N-[(3R)-7-{3,8- diazabicyclo[3.2.1]octan-3-yl}-6-fluoro-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

105. 3-amino-N-[(3R)-8-fluoro-7-{9-oxa-3,7- diazabicyclo[3.3.1]nonan-3-yl}-3,4-dihydro- 2H-1-benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

106. 3-amino-N-[(3R)-6-fluoro-7-{9-oxa-3,7- diazabicyclo[3.3.1]nonan-3-yl}-3,4-dihydro- 2H-1-benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

107. 7-amino-N-[(3R)-7-{3,8- diazabicyclo[3.2.1]octan-3-yl}-5,8-difluoro- 3,4-dihydro-2H-1-benzopyran-3-yl]-3- methylthieno[2,3-b]pyrazine-6-carboxamide

108. 6-amino-N-[(3R)-7-{3,8- diazabicyclo[3.2.1]octan-3-yl}-5,6-difluoro- 3,4-dihydro-2H-1-benzopyran-3-yl]-2- methylthieno[2,3-d][1,3]thiazole-5- carboxamide

109. 3-amino-N-[(2S)-7-cyano-6-{9-oxa-3,7- diazabicyclo[3.3.1]nonan-3-yl}-1,2,3,4- tetrahydronaphthalen-2-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

110. 3-amino-N-[(3R)-7-[(1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]-5,8-difluoro- 3,4-dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

111. 3-amino-N-[(3R)-7-[(1R,4R)-2,5- diazabicyclo[2.2.1]heptan-2-yl]-5,8-difluoro- 3,4-dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

112. 3-amino-N-[(3R)-7-[(1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]-5,6-difluoro- 3,4-dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

113. 3-amino-N-[(3R)-7-{9,9-difluoro-3,7- diazabicyclo[3.3.1]nonan-3-yl}-2H,3H,4H- pyrano[2,3-b]pyridin-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

114. 3-amino-N-[(3R)-7-{9,9-difluoro-3,7- diazabicyclo[3.3.1]nonan-3-yl}-2H,3H,4H- pyrano[3,2-c]pyridin-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

115. 3-amino-N-[(3R)-7-[(3S,4S)-3-amino- 4-ethoxypyrrolidin-1-yl]-3,4-dihydro-2H-1- benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

116. 3-amino-N-[(2S)-6-[(3S,4S)-3-amino-4- methoxypyrrolidin-1-yl]-1,2,3,4- tetrahydronaphthalen-2-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

117. 7-amino-N-[(3R)-7-[(3S,4S)-3-amino- 4-methoxypyrrolidin-1-yl]-3,4-dihydro-2H-1- benzopyran-3-yl]-3-methylthieno[2,3- b]pyrazine-6-carboxamide

118. 6-amino-N-[(3R)-7-[(3S,4S)-3-amino- 4-methoxpyrrolidin-1-yl]-3,4-dihydro-2H-1- benzopyran-3-yl]-2-methylthieno[2,3- d][1,3]thiazole-5-carboxamide

119. 3-amino-N-[(3R)-7-[(3S,4S)-3-amino- 4-methoxypiperidin-1-yl]-3,4-dihydro-2H-1- benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

120. 3-amino-N-[(3R)-7-[(3R,4R)-3-amino- 4-methoxypiperidin-1-yl]-3,4-dihydro-2H-1- benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

121. 3-amino-N-[(3R)-7-[(3S,4R)-3-amino- 4-methoxpyrrolidin-1-yl]-3,4-dihydro-2H-1- benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

122. 3-amino-N-[(3R)-7-[(3R,4S)-3-amino- 4-methoxypyrrolidin-1-yl]-3,4-dihydro-2H-1- benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

123. 3-amino-6-methyl-N-[(3R)-7-[(1s,3S)- 3-aminocyclobutyl]-3,4-dihydro-2H-1- benzopyran-3-yl]thieno[2,3-b]pyridine-2- carboxamide

124. 3-amino-6-methyl-N-[(3R)-7-[(1r,3r)-3- aminocyclobutyl]-3,4-dihydro-2H-1- benzopyran-3-yl]thieno[2,3-b]pyridine-2- carboxamide

125. 3-amino-6-methyl-N-[(3R)-7-{3-oxa-9- azabicyclo[3.3.1]nonan-7-yl}-3,4-dihydro- 2H-1-benzopyran-3-yl]thieno[2,3-b]pyridine- 2-carboxamide

126. 3-amino-N-[(3R)-6-cyano-7-{3,8- diazabicyclo[3.2.1]octan-3-yl}-5-fluoro-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

127. 3-amino-N-[(3R)-6-cyano-5-fluoro-7- {9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl}- 3,4-dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

128. 3-amino-N-[(3R)-7-[(3S,4S)-4-amino- 3-methoxypiperidin-1-yl]-3,4-dihydro-2H-1- benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

129. 3-amino-N-[(3R)-7-[(3R,4R)-4-amino- 3-methoxypiperidin-1-yl]-3,4-dihydro-2H-1- benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

130. 7-amino-N-[(2S)-6-[(3S,4S)-3-amino-4- methoxypyrrolidin-1-yl]-1,2,3,4- tetrahydronaphthalen-2-yl]-3- methylthieno[2,3-b]pyrazine-6-carboxamide

131. N-[(2S)-6-[(3S,4S)-3-amino-4- methoxypyrrolidin-1-yl]-1,2,3,4- tetrahydronaphthalen-2-yl]-7-ethyl-7H- pyrrolo[2,3-c]pyridazine-3-carboxamide

132. N-[(2S)-6-[(3S,4S)-3-amino-4- methoxypyrrolidin-1-yl]-1,2,3,4- tetrahydronaphthalen-2-yl]-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5-carboxamide

133. 6-amino-N-[(2S)-6-[(3S,4S)-3-amino-4- methoxypyrrolidin-1-yl]-1,2,3,4- tetrahydronaphthalen-2-yl]-2- methylthieno[2,3-d][1,3]thiazole-5- carboxamide

134. 3-amino-N-[(2S)-6-[(3S,4S)-3-amino-4- methoxypyrrolidin-1-yl]-1,2,3,4- tetrahydronaphthalen-2-yl]-6- methoxythieno[2,3-b]pyridine-2- carboxamide

135. 3-amino-N-[(2S)-6-[(3S,4S)-3-amino-4- methoxypyrrolidin-1-yl]-1,2,3,4- tetrahydronaphthalen-2-yl]-5-fluoro-6- methoxythieno[2,3-b]pyridine-2- carboxamide

136. 3-amino-N-[(2S)-6-[(3S,4S)-3-amino-4- methoxpyrrolidin-1-yl]-8-fluoro-1,2,3,4- tetrahydronaphthalen-2-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

137. 3-amino-N-[(2R)-6-[(3S,4S)-3-amino- 4-methoxypyrrolidin-1-yl]-8-fluoro-1,2,3,4- tetrahydronaphthalen-2-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

138. N-[(2S)-6-[(3S,4S)-3-amino-4- methoxypyrrolidin-1-yl]-8-fluoro-1,2,3,4- tetrahydronaphthalen-2-yl]-7-ethyl-7H- pyrrolo[2,3-c]pyridazine-3-carboxamide

139. N-[(2R)-6-[(3S,4S)-3-amino-4- methoxpyrrolidin-1-yl]-8-fluoro-1,2,3,4- tetrahydronaphthalen-2-yl]-7-ethyl-7H- pyrrolo[2,3-c]pyridazine-3-carboxamide

140. 3-amino-N-[(3R)-7-[(3S,4S)-3-amino- 4-cyclopropoxpyrrolidin-1-yl]-3,4-dihydro- 2H-1-benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

141. 3-amino-N-[(3R)-7-[(3S,4S)-3-amino- 4-cyclobutoxpyrrolidin-1-yl]-3,4-dihydro- 2H-1-benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

142. 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4- ethoxypyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

143. 3-amino-N-[(2S)-6-[(3S,4R)-3-amino- 4-methoxypyrrolidin-1-yl]-1,2,3,4- tetrahydronaphthalen-2-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

144. 3-amino-N-[(2S)-6-[(3R,4S)-3-amino- 4-methoxypyrrolidin-1-yl]-1,2,3,4- tetrahydronaphthalen-2-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

145. 3-amino-N-[(3R)-7-[(3S,4R)-3-amino- 4-methoxpyrrolidin-1-yl]-5-fluoro-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

146. 3-amino-N-[(3R)-7-[(3R,4S)-3-amino- 4-methoxypyrrolidin-1-yl]-5-fluoro-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

147. 7-amino-N-[(3R)-7-[(3S,4R)-3-amino- 4-methoxypyrrolidin-1-yl]-3,4-dihydro-2H-1- benzopyran-3-yl]-3-methylthieno[2,3- b]pyrazine-6-carboxamide

148. 7-amino-N-[(3R)-7-[(3R,4S)-3-amino- 4-methoxpyrrolidin-1-yl]-3,4-dihydro-2H-1- benzopyran-3-yl]-3-methylthieno[2,3- b]pyrazine-6-carboxamide

149. 6-amino-N-[(3R)-7-[(3S,4R)-3-amino- 4-methoxypyrrolidin-1-yl]-3,4-dihydro-2H-1- benzopyran-3-yl]-2-methylthieno[2,3- d][1,3]thiazole-5-carboxamide

150. 6-amino-N-[(3R)-7-[(3R,4S)-3-amino- 4-methoxypyrrolidin-1-yl]-3,4-dihydro-2H-1- benzopyran-3-yl]-2-methylthieno[2,3- d][1,3]thiazole-5-carboxamide

151. 3-amino-N-[(3R)-7-[(3S,4R)-3-amino- 4-ethoxypyrrolidin-1-yl]-3,4-dihydro-2H-1- benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

152. 3-amino-N-[(3R)-7-[(3R,4S)-3-amino- 4-ethoxpyrrolidin-1-yl]-3,4-dihydro-2H-1- benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

153. N-[(3R)-7-[(4aS,7aR)- octahydropyrrolo[3,4-b]morpholin-6-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

154. N-[(3R)-7-[(4aR,7aS)- octahydropyrrolo[3,4-b]morpholin-6-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

155. 3-amino-N-[(3R)-7-[(2S)-2- (methoxymethyl)piperazin-1-yl]-3,4-dihydro- 2H-1-benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

156. 3-amino-N-[(3R)-7-[(2R)-2- (methoxymethyl)piperazin-1-yl]-3,4-dihydro- 2H-1-benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

157. 3-amino-N-[(3R)-7-[(3R)-3- (methoxymethyl)piperazin-1-yl]-3,4-dihydro- 2H-1-benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

158. 3-amino-N-[(3R)-7-[(3S)-3- (methoxymethyl)piperazin-1-yl]-3,4-dihydro- 2H-1-benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

159. 3-amino-N-[(3R)-5,6-difluoro-7- (piperazin-1-yl)-3,4-dihydro-2H-1- benzopyran-3-yl]-4,6-dimethylthieno[2,3- b]pyridine-2-carboxamide

160. 3-amino-N-[(3S)-5,6-difluoro-7- (piperazin-1-yl)-3,4-dihydro-2H-1- benzopyran-3-yl]-4,6-dimethylthieno[2,3- b]pyridine-2-carboxamide

161. 3-amino-N-[(3R)-7-[(3R,4R)-3-amino- 4-(methoxymethyl)pyrrolidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

162. 3-amino-N-[(3R)-7-[(3S,4S)-3-amino- 4-(methoxymethyl)pyrrolidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

163. 3-amino-N-[(3R)-7-[(3S,4R)-3-amino- 4-(methoxymethyl)pyrrolidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

164. 3-amino-N-[(3R)-7-[(3R,4S)-3-amino- 4-(methoxymethyl)pyrrolidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

165. N-[(3R)-7-[(3aR,6aR)- octahydropyrrolo[2,3-c]pyrrol-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

166. N-[(3R)-7-[(3aS,6aS)- octahydropyrrolo[2,3-c]pyrrol-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

167. 3-amino-N-[(3R)-7-[(3R,4R)-3-amino- 4-(difluoromethyl)pyrrolidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

168. 3-amino-N-[(3R)-7-[(3S,4S)-3-amino- 4-(difluoromethyl)pyrrolidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

169. 3-amino-N-[(3R)-5-fluoro-7-(piperazin- 1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-6- methylfuro[2,3-b]pyridine-2-carboxamide

170. 3-amino-N-[(3R)-7-{3,8- diazabicyclo[3.2.1]octan-3-yl}-5-fluoro-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylfuro[2,3-b]pyridine-2-carboxamide

171. 3-amino-N-[(2S)-6-{3,8- diazabicyclo[3.2.1]octan-3-yl}-1,2,3,4- tetrahydronaphthalen-2-yl]-6- methylfuro[2,3-b]pyridine-2-carboxamide

172. 3-amino-N-[(3R)-7-{3,8- diazabicyclo[3.2.1]octan-3-yl}-5,8-difluoro- 3,4-dihydro-2H-1-benzopyran-3-yl]-6- methylfuro[2,3-b]pyridine-2-carboxamide

173. 3-amino-N-[(3R)-7-{3,8- diazabicyclo[3.2.1]octan-3-yl}-2H,3H,4H- pyrano[2,3-b]pyridin-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

174. 7-amino-N-[(3R)-7-[(3S,4S)-3-amino- 4-methoxpyrrolidin-1-yl]-8-cyano-5-fluoro- 3,4-dihydro-2H-1-benzopyran-3-yl]-3- methylthieno[2,3-b]pyrazine-6-carboxamide

175. 3-amino-N-[(3R)-7-[(3S,4S)-3-amino- 4-methoxypyrrolidin-1-yl]-8-cyano-5-fluoro- 3,4-dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

176. 7-amino-N-[(3R)-7-[(3S,4S)-3-amino- 4-methoxpyrrolidin-1-yl]-6-cyano-3,4- dihydro-2H-1-benzopyran-3-yl]-3- methylthieno[2,3-b]pyrazine-6-carboxamide

177. 3-amino-N-[(3R)-7-[(3S,4S)-3-amino- 4-methoxypyrrolidin-1-yl]-6-cyano-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

178. 3-amino-N-[(2S)-6-[(3S,4S)-3-amino-4- methoxpyrrolidin-1-yl]-5-cyano-1,2,3,4- tetrahydronaphthalen-2-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

179. 3-amino-N-[(3R)-7-[(3S,4S)-3-amino- 4-methoxypyrrolidin-1-yl]-2H,3H,4H- pyrano[3,2-c]pyridin-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

180. 3-amino-N-[(3R)-7-[(3S,4S)-3-amino- 4-ethoxypyrrolidin-1-yl]-2H,3H,4H- pyrano[3,2-c]pyridin-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

181. 7-amino-N-[(3R)-7-[(3S,4S)-3-amino- 4-methoxypyrrolidin-1-yl]-2H,3H,4H- pyrano[2,3-b]pyridin-3-yl]-3- methylthieno[2,3-b]pyrazine-6-carboxamide

182. 7-amino-N-[(3R)-7-[(3S,4S)-3-amino- 4-ethoxypyrrolidin-1-yl]-2H,3H,4H- pyrano[2,3-b]pyridin-3-yl]-3- methylthieno[2,3-b]pyrazine-6-carboxamide

183. 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4- methoxypyrrolidin-1-yl]-3-fluoro-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

184. N-[(3R)-7-[(4aR,7aS)- octahydropyrrolo[3,4-b]morpholin-4-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

185. N-[(3R)-7-[(4aS,7aR)- octahydropyrrolo[3,4-b]morpholin-4-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

186. 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4- methoxypyrrolidin-1-yl]-5,6,7,8- tetrahydroquinazolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

187. 3-amino-N-[(6R)-2-[(3S,4S)-3-amino- 4-methoxypyrrolidin-1-yl]-5,6,7,8- tetrahydroquinazolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

188. N-[(2S)-6-[(3S,4S)-3-amino-4- methoxypyrrolidin-1-yl]-1,2,3,4- tetrahydronaphthalen-2-yl]- 5H,6H,6aH,7H,7aH-cyclopropa[c]1,8- naphthyridine-2-carboxamide

189. (6aS,7aR)-N-[(2S)-6-[(3S,4S)-3- amino-4-methoxypyrrolidin-1-yl]-1,2,3,4- tetrahydronaphthalen-2-yl]- 5H,6H,6aH,7H,7aH-cyclopropa[c]1,8- naphthyridine-2-carboxamide

190. (6aR,7aS)-N-[(2S)-6-[(3S,4S)-3- amino-4-methoxypyrrolidin-1-yl]-1,2,3,4- tetrahydronaphthalen-2-yl]- 5H,6H,6aH,7H,7aH-cyclopropa[c]1,8- naphthyridine-2-carboxamide

191. (6aS,7aR)-N-[(2S)-6-{3,8- diazabicyclo[3.2.1]octan-3-yl}-8-fluoro- 1,2,3,4-tetrahydronaphthalen-2-yl]- 5H,6H,6aH,7H,7aH-cyclopropa[c]1,8- naphthyridine-2-carboxamide

192. (6aR,7aS)-N-[(2S)-6-{3,8- diazabicyclo[3.2.1]octan-3-yl}-8-fluoro- 1,2,3,4-tetrahydronaphthalen-2-yl]- 5H,6H,6aH,7H,7aH-cyclopropa[c]1,8- naphthyridine-2-carboxamide

193. (6aS,7aR)-N-[(2R)-6-{3,8- diazabicyclo[3.2.1]octan-3-yl}-8-fluoro- 1,2,3,4-tetrahydronaphthalen-2-yl]- 5H,6H,6aH,7H,7aH-cyclopropa[c]1,8- naphthyridine-2-carboxamide

194. (6aR,7aS)-N-[(2R)-6-{3,8- diazabicyclo[3.2.1]octan-3-yl}-8-fluoro- 1,2,3,4-tetrahydronaphthalen-2-yl]- 5H,6H,6aH,7H,7aH-cyclopropa[c]1,8- naphthyridine-2-carboxamide

195. (6aS,7aR)-N-[(2S)-5-cyano-6-{3,8- diazabicyclo[3.2.1]octan-3-yl}-8-fluoro- 1,2,3,4-tetrahydronaphthalen-2-yl]- 5H,6H,6aH,7H,7aH-cyclopropa[c]1,8- naphthyridine-2-carboxamide

196. (6aR,7aS)-N-[(2S)-5-cyano-6-{3,8- diazabicyclo[3.2.1]octan-3-yl}-8-fluoro- 1,2,3,4-tetrahydronaphthalen-2-yl]- 5H,6H,6aH,7H,7aH-cyclopropa[c]1,8- naphthyridine-2-carboxamide

197. (6aS,7aR)-N-[(2R)-5-cyano-6-{3,8- diazabicyclo[3.2.1]octan-3-yl}-8-fluoro- 1,2,3,4-tetrahydronaphthalen-2-yl]- 5H,6H,6aH,7H,7aH-cyclopropa[c]1,8- naphthyridine-2-carboxamide

198. (6aR,7aS)-N-[(2R)-5-cyano-6-{3,8- diazabicyclo[3.2.1]octan-3-yl}-8-fluoro- 1,2,3,4-tetrahydronaphthalen-2-yl]- 5H,6H,6aH,7H,7aH-cyclopropa[c]1,8- naphthyridine-2-carboxamide

199. 7-amino-N-[(3R)-7-[(3S,4S)-3-amino- 4-methoxypyrrolidin-1-yl]-6-cyano-5-fluoro- 3,4-dihydro-2H-1-benzopyran-3-yl]-3- methylthieno[2,3-b]pyrazine-6-carboxamide

200. 3-amino-N-[(3R)-7-[(3S,4S)-3-amino- 4-methoxypyrrolidin-1-yl]-6-cyano-5-fluoro- 3,4-dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

201. 3-amino-N-[(2S)-6-[(3S,4S)-3-amino-4- methoxypyrrolidin-1-yl]-7-cyano-1,2,3,4- tetrahydronaphthalen-2-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

202. 3-amino-N-[(3R)-7-[(3S,4S)-3-amino- 4-(propan-2-yloxy)pyrrolidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

203. 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4- methoxypyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-5-fluoro-6- methylthieno[2,3-b]pyridine-2-carboxamide

204. 3-amino-5-fluoro-6-methyl-N-[(6S)-2- (piperazin-1-yl)-5,6,7,8-tetrahydroquinolin- 6-yl]thieno[2,3-b]pyridine-2-carboxamide

205. 3-amino-6-methyl-N-[(6S,8S)-8- methyl-2-(piperazin-1-yl)-5,6,7,8- tetrahydroquinolin-6-yl]thieno[2,3- b]pyridine-2-carboxamide

206. 3-amino-6-methyl-N-[(6R,8S)-8- methyl-2-(piperazin-1-yl)-5,6,7,8- tetrahydroquinolin-6-yl]thieno[2,3- b]pyridine-2-carboxamide

207. 3-amino-6-methyl-N-[(6S,8R)-8- methyl-2-(piperazin-1-yl)-5,6,7,8- tetrahydroquinolin-6-yl]thieno[2,3- b]pyridine-2-carboxamide

208. 3-amino-6-methyl-N-[(6R,8R)-8- methyl-2-(piperazin-1-yl)-5,6,7,8- tetrahydroquinolin-6-yl]thieno[2,3- b]pyridine-2-carboxamide

209. 3-amino-6-methyl-N-[(3R)-7-{3-oxa- 7,9-diazabicyclo[3.3.1]nonan-9-yl}-3,4- dihydro-2H-1-benzopyran-3-yl]thieno[2,3- b]pyridine-2-carboxamide

210. 3-amino-N-[(6S)-2-[(3S,4S)-4-amino-3- methoxy-3-methylpyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

211. 3-amino-N-[(6S)-2-[(3R,4R)-4-amino- 3-methoxy-3-methylpyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

212. 3-amino-N-[(3R)-7-[(3S,4S)-3- methoxy-4-(methylamino)pyrrolidin-1-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

213. 3-amino-N-[(3R)-7-[(3S,4S)-3- acetamido-4-methoxypyrrolidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

214. 3-amino-N-[(3R)-7-[(4R)-4-amino-3,3- dimethylpyrrolidin-1-yl]-3,4-dihydro-2H-1- benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

215. 3-amino-N-[(3R)-7-[(4S)-4-amino-3,3- dimethylpyrrolidin-1-yl]-3,4-dihydro-2H-1- benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

216. N-[(6S)-2-[(3aS,6aS)- octahydropyrrolo[2,3-c]pyrrol-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

217. N-[(6S)-2-[(3aR,6aR)- octahydropyrrolo[2,3-c]pyrrol-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

218. N-[(6S)-2-[(3aS,6aS)- octahydropyrrolo[2,3-c]pyrrol-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-3-amino-4,6- dimethylthieno[2,3-b]pyridine-2- carboxamide

219. N-[(6S)-2-[(3aR,6aR)- octahydropyrrolo[2,3-c]pyrrol-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-3-amino-4,6- dimethylthieno[2,3-b]pyridine-2- carboxamide

220. N-[(3R)-7-[(3aS,6aS)- octahydropyrrolo[2,3-c]pyrrol-1-yl]-5-fluoro- 3,4-dihydro-2H-1-benzopyran-3-yl]-3- amino-6-methylthieno[2,3-b]pyridine-2- carboxamide

221. N-[(3R)-7-[(3aR,6aR)- octahydropyrrolo[2,3-c]pyrrol-1-yl]-5-fluoro- 3,4-dihydro-2H-1-benzopyran-3-yl]-3- amino-6-methylthieno[2,3-b]pyridine-2- carboxamide

222. N-[(3R)-7-[(3aS,6aS)- octahydropyrrolo[2,3-c]pyrrol-1-yl]-5-fluoro- 3,4-dihydro-2H-1-benzopyran-3-yl]-3- amino-4,6-dimethylthieno[2,3-b]pyridine-2- carboxamide

223. N-[(3R)-7-[(3aR,6aR)- octahydropyrrolo[2,3-c]pyrrol-1-yl]-5-fluoro- 3,4-dihydro-2H-1-benzopyran-3-yl]-3- amino-4,6-dimethylthieno[2,3-b]pyridine-2- carboxamide

224. N-[(3R)-7-[(3aR,7aS)-octahydro-1H- pyrrolo[2,3-c]pyridin-1-yl]-3,4-dihydro-2H-1- benzopyran-3-yl]-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

225. N-[(3R)-7-[(3aS,7aR)-octahydro-1H- pyrrolo[2,3-c]pyridin-1-yl]-3,4-dihydro-2H-1- benzopyran-3-yl]-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

226. N-[(3R)-7-[(3aS,6aS)- octahydropyrrolo[2,3-c]pyrrol-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-3-amino- 4,6-dimethylthieno[2,3-b]pyridine-2- carboxamide

227. N-[(3R)-7-[(3aR,6aR)- octahydropyrrolo[2,3-c]pyrrol-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-3-amino- 4,6-dimethylthieno[2,3-b]pyridine-2- carboxamide

228. (6aS,7aR)-N-[(3R)-8-cyano-7-{3,8- diazabicyclo[3.2.1]octan-3-yl}-5-fluoro-3,4- dihydro-2H-1-benzopyran-3-yl]- 5H,6H,6aH,7H,7aH-cyclopropa[c]1,8- naphthyridine-2-carboxamide

229. (6aR,7aS)-N-[(3R)-8-cyano-7-{3,8- diazabicyclo[3.2.1]octan-3-yl}-5-fluoro-3,4- dihydro-2H-1-benzopyran-3-yl]- 5H,6H,6aH,7H,7aH-cyclopropa[c]1,8- naphthyridine-2-carboxamide

230. 3-amino-N-[(3R)-8-cyano-7-{3,8- diazabicyclo[3.2.1]octan-3-yl}-5-fluoro-3,4- dihydro-2H-1-benzopyran-3-yl]-4,6- dimethylthieno[2,3-b]pyridine-2- carboxamide

231. N-[(3R)-7-[(3aR,6R,7aR)-6-amino- octahydro-1H-indol-1-yl]-3,4-dihydro-2H-1- benzopyran-3-yl]-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

232. N-[(3R)-7-[(3aR,6S,7aR)-6-amino- octahydro-1H-indol-1-yl]-3,4-dihydro-2H-1- benzopyran-3-yl]-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

233. N-[(3R)-7-[(3aS,6R,7aS)-6-amino- octahydro-1H-indol-1-yl]-3,4-dihydro-2H-1- benzopyran-3-yl]-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

234. N-[(3R)-7-[(3aS,6S,7aS)-6-amino- octahydro-1H-indol-1-yl]-3,4-dihydro-2H-1- benzopyran-3-yl]-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

235. N-[(3R)-7-[(3aS,7aR)-octahydro-1H- pyrrolo[3,2-c]pyridin-1-yl]-3,4-dihydro-2H-1- benzopyran-3-yl]-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

236. N-[(3R)-7-[(3aR,7aS)-octahydro-1H- pyrrolo[3,2-c]pyridin-1-yl]-3,4-dihydro-2H-1- benzopyran-3-yl]-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

237. N-[(3R)-7-[(4aR,7aR)-4,4-difluoro- octahydro-1H-pyrrolo[3,4-b]pyridin-6-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

238. N-[(3R)-7-[(4aS,7aS)-4,4-difluoro- octahydro-1H-pyrrolo[3,4-b]pyridin-6-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

239. 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4- methoxy-3-methylpyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

240. 3-amino-N-[(6S)-2-[(3R,4R)-3-amino- 4-methoxy-3-methylpyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

241. 3-amino-N-[(3R)-6-cyano-7-{3,8- diazabicyclo[3.2.1]octan-3-yl}-5-fluoro-3,4- dihydro-2H-1-benzopyran-3-yl]-4,6- dimethylthieno[2,3-b]pyridine-2- carboxamide

242. N-[(3R)-7-[(4aR,7aR)-octahydro-1H- pyrrolo[3,4-b]pyridin-1-yl]-3,4-dihydro-2H-1- benzopyran-3-yl]-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

243. N-[(3R)-7-[(4aS,7aS)-octahydro-1H- pyrrolo[3,4-b]pyridin-1-yl]-3,4-dihydro-2H-1- benzopyran-3-yl]-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

244. 3-amino-N-[(3R)-7-[(2R,5R)-5-amino- 2-(trifluoromethyl)piperidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

245. 3-amino-N-[(3R)-7-[(2S,5S)-5-amino- 2-(trifluoromethyl)piperidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

246. 3-amino-N-[(3R)-7-[(2R,5S)-5-amino- 2-(trifluoromethyl)piperidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

247. 3-amino-N-[(3R)-7-[(2S,5R)-5-amino- 2-(trifluoromethyl)piperidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

248. N-[(3R)-7-[(3aS)-3a-amino- octahydrocyclopenta[c]pyrrol-2-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

249. N-[(3R)-7-[(3aR)-3a-amino- octahydrocyclopenta[c]pyrrol-2-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

250. 3-amino-N-[(3R)-7-[(3R,4R)-3-amino- 4-(methoxymethyl)pyrrolidin-1-yl]-5-fluoro- 3,4-dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

251. 3-amino-N-[(3R)-7-[(3S,4S)-3-amino- 4-(methoxymethyl)pyrrolidin-1-yl]-5-fluoro- 3,4-dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

252. 3-amino-N-[(2S)-6-[(3R,4R)-3-amino- 4-(methoxymethyl)pyrrolidin-1-yl]-1,2,3,4- tetrahydronaphthalen-2-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

253. 3-amino-N-[(2S)-6-[(3S,4S)-3-amino-4- (methoxymethyl)pyrrolidin-1-yl]-1,2,3,4- tetrahydronaphthalen-2-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

254. 3-amino-N-[(6S)-2-[(3S,4R)-3-amino- 4-ethoxypyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

255. 3-amino-N-[(6S)-2-[(3R,4S)-3-amino- 4-ethoxypyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

256. 3-amino-N-[(3R)-7-[(4S)-4-amino-3,3- difluoropyrrolidin-1-yl]-3,4-dihydro-2H-1- benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

257. 3-amino-N-[(3R)-7-[(4R)-4-amino-3,3- difluoropyrrolidin-1-yl]-3,4-dihydro-2H-1- benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

258. 3-amino-N-[(3R)-7-[(8R)-8-amino-2- oxa-6-azaspiro[3.4]octan-6-yl]-3,4-dihydro- 2H-1-benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

259. 3-amino-N-[(3R)-7-[(8S)-8-amino-2- oxa-6-azaspiro[3.4]octan-6-yl]-3,4-dihydro- 2H-1-benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

260. 3-amino-N-[(3R)-7-[(2S,4R)-4-amino- 2-(methoxymethyl)pyrrolidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

261. 3-amino-N-[(3R)-7-[(2R,4S)-4-amino- 2-(methoxymethyl)pyrrolidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

262. 3-amino-N-[(3R)-7-[(2R,4R)-4-amino- 2-(methoxymethyl)pyrrolidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

263. 3-amino-N-[(3R)-7-[(2S,4S)-4-amino- 2-(methoxymethyl)pyrrolidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

264. (6aS,7aR)-N-[(3R)-6-cyano-7-{3,8- diazabicyclo[3.2.1]octan-3-yl}-5-fluoro-3,4- dihydro-2H-1-benzopyran-3-yl]- 5H,6H,6aH,7H,7aH-cyclopropa[c]1,8- naphthyridine-2-carboxamide

265. (6aR,7aS)-N-[(3R)-6-cyano-7-{3,8- diazabicyclo[3.2.1]octan-3-yl}-5-fluoro-3,4- dihydro-2H-1-benzopyran-3-yl]- 5H,6H,6aH,7H,7aH-cyclopropa[c]1,8- naphthyridine-2-carboxamide

266. 7-amino-N-[(6S)-2-[(3S,4S)-3- acetamido-4-methoxypyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-3- methylthieno[2,3-b]pyrazine-6-carboxamide

267. 3-amino-N-[(2S)-6-[(3S,4R)-3-amino- 4-ethoxypyrrolidin-1-yl]-1,2,3,4- tetrahydronaphthalen-2-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

268. 3-amino-N-[(2S)-6-[(3R,4S)-3-amino- 4-ethoxypyrrolidin-1-yl]-1,2,3,4- tetrahydronaphthalen-2-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

269. 3-amino-N-[(6S)-2-[(3S,4R)-3-amino- 4-methoxypyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

270. 3-amino-N-[(6S)-2-[(3R,4S)-3-amino- 4-methoxypyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

271. 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4- (propan-2-yloxy)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinazolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

272. 3-amino-N-[(6R)-2-[(3S,4S)-3-amino- 4-(propan-2-yloxy)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinazolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

273. 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4- methoxypyrrolidin-1-yl]-5,6,7,8- tetrahydroquinazolin-6-yl]-4,6- dimethylthieno[2,3-b]pyridine-2- carboxamide

274. 3-amino-N-[(6R)-2-[(3S,4S)-3-amino- 4-methoxypyrrolidin-1-yl]-5,6,7,8- tetrahydroquinazolin-6-yl]-4,6- dimethylthieno[2,3-b]pyridine-2- carboxamide

275. 3-amino-N-[(3R)-7-[(3R,4R)-3-amino- 4-(methoxymethyl)pyrrolidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-4,6- dimethylthieno[2,3-b]pyridine-2- carboxamide

276. 3-amino-N-[(3R)-7-[(3S,4S)-3-amino- 4-(methoxymethyl)pyrrolidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-4,6- dimethylthieno[2,3-b]pyridine-2- carboxamide

277. 3-amino-N-[(3R)-7-[(3R,4R)-3-amino- 4-(methoxymethyl)pyrrolidin-1-yl]-5,8- difluoro-3,4-dihydro-2H-1-benzopyran-3-yl]- 4,6-dimethylthieno[2,3-b]pyridine-2- carboxamide

278. 3-amino-N-[(3R)-7-[(3S,4S)-3-amino- 4-(methoxymethyl)pyrrolidin-1-yl]-5,8- difluoro-3,4-dihydro-2H-1-benzopyran-3-yl]- 4,6-dimethylthieno[2,3-b]pyridine-2- carboxamide

279. 7-amino-N-[(6S)-2-[(3S,4S)-4-amino-3- methoxy-3-methylpyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-3-methylthieno[2,3- b]pyrazine-6-carboxamide

280. 7-amino-N-[(6S)-2-[(3R,4R)-4-amino- 3-methoxy-3-methylpyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-3-methylthieno[2,3- b]pyrazine-6-carboxamide

281. 3-amino-N-[(3R)-7-[(3S,4S)-4-amino- 3-methoxy-3-methylpyrrolidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

282. 3-amino-N-[(3R)-7-[(3R,4R)-4-amino- 3-methoxy-3-methylpyrrolidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

283. 3-amino-N-[(3R)-7-[(2S,3R,4S)-4- amino-3-methoxy-2-methylpyrrolidin-1-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

284. 3-amino-N-[(3R)-7-[(2R,3S,4R)-4- amino-3-methoxy-2-methylpyrrolidin-1-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

285. 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4- cyclobutoxypyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

286. 3-amino-N-[(3R)-7-[(3S,4S)-3-amino- 4-methoxypyrrolidin-1-yl]-2H,3H,4H- pyrano[2,3-b]pyridin-3-yl]-4,6- dimethylthieno[2,3-b]pyridine-2- carboxamide

287. 3-amino-N-[(3R)-7-[(3S,4S)-3-amino- 4-(propan-2-yloxy)pyrrolidin-1-yl]- 2H,3H,4H-pyrano[2,3-b]pyridin-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

288. 3-amino-N-[(3R)-7-[(3R)-3- aminopyrrolidin-1-yl]-3,4-dihydro-2H-1- benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

289. N-[(3R)-7-[(3aR,6aS)-3a-methoxy- octahydropyrrolo[2,3-c]pyrrol-5-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

290. N-[(3R)-7-[(3aS,6aR)-3a-methoxy- octahydropyrrolo[2,3-c]pyrrol-5-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

291. N-[(3R)-7-[(3aS,6aS)-3a-methoxy- octahydropyrrolo[3,4-c]pyrrol-2-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

292. N-[(3R)-7-[(3aR,6aR)-3a-methoxy- octahydropyrrolo[3,4-c]pyrrol-2-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

293. 3-amino-N-[(6S)-2-[(3S,4S)-3- acetamido-4-methoxypyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-4,6- dimethylthieno[2,3-b]pyridine-2- carboxamide

294. 3-amino-N-[(3R)-7-[(3R,4S)-3-amino- 4-(difluoromethyl)pyrrolidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

295. 3-amino-N-[(3R)-7-[(3S,4R)-3-amino- 4-(difluoromethyl)pyrrolidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

296. 3-amino-N-[(6S)-2-[(3R,4R)-3-amino- 4-(methoxymethyl)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-4,6- dimethylthieno[2,3-b]pyridine-2- carboxamide

297. 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4- (methoxymethyl)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-4,6- dimethylthieno[2,3-b]pyridine-2- carboxamide

298. 7-amino-N-[(6S)-2-[(3R,4R)-3-amino- 4-(methoxymethyl)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-3-methylthieno[2,3- b]pyrazine-6-carboxamide

299. 7-amino-N-[(6S)-2-[(3S,4S)-3-amino-4- (methoxymethyl)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-3-methylthieno[2,3- b]pyrazine-6-carboxamide

300. 3-amino-N-[(6S)-2-[(3R,4R)-3-amino- 4-(methoxymethyl)pyrrolidin-1-yl]-3-fluoro- 5,6,7,8-tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

301. 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4- (methoxymethyl)pyrrolidin-1-yl]-3-fluoro- 5,6,7,8-tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

302. 3-amino-N-[(6R)-2-[(3R,4R)-3-amino- 4-(methoxymethyl)pyrrolidin-1-yl]-3-fluoro- 5,6,7,8-tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

303. 3-amino-N-[(6R)-2-[(3S,4S)-3-amino- 4-(methoxymethyl)pyrrolidin-1-yl]-3-fluoro- 5,6,7,8-tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

304. N-[(3R)-7-[(3aS,6aS)- octahydropyrrolo[3,4-b]pyrrol-5-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

305. N-[(3R)-7-[(3aR,6aR)- octahydropyrrolo[3,4-b]pyrrol-5-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

306. 3-amino-N-[(3R)-7-{2,6- diazaspiro[3.4]octan-6-yl}-3,4-dihydro-2H-1- benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

307. 3-amino-N-[(3R)-7-[(5S,9S)-9-amino- 1-oxa-7-azaspiro[4.4]nonan-7-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

308. 3-amino-N-[(3R)-7-[(5R,9R)-9-amino- 1-oxa-7-azaspiro[4.4]nonan-7-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

309. 3-amino-N-[(3R)-7-[(5S,9R)-9-amino- 1-oxa-7-azaspiro[4.4]nonan-7-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

310. 3-amino-N-[(3R)-7-[(5R,9S)-9-amino- 1-oxa-7-azaspiro[4.4]nonan-7-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

311. 3-amino-N-[(6S)-2-[(3S,4S)-3- methoxy-4-(methylamino)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

312. 3-amino-N-[(6S)-2-[(3S,4S)-3- methoxy-4-(methylamino)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-4,6- dimethylthieno[2,3-b]pyridine-2- carboxamide

313. 3-amino-N-[(3R)-7-[(3R,4R)-3-amino- 4-(ethoxymethyl)pyrrolidin-1-yl]-3,4-dihydro- 2H-1-benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

314. 3-amino-N-[(3R)-7-[(3S,4S)-3-amino- 4-(ethoxymethyl)pyrrolidin-1-yl]-3,4-dihydro- 2H-1-benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

315. 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4- methoxypiperidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

316. 3-amino-N-[(6S)-2-[(3R,4R)-3-amino- 4-methoxypiperidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

317. 3-amino-N-[(3R)-7-[(3S,4S)-3-amino- 4-methoxypiperidin-1-yl]-3,4-dihydro-2H-1- benzopyran-3-yl]-4,6-dimethylthieno[2,3- b]pyridine-2-carboxamide

318. 3-amino-N-[(3R)-7-[(3R,4R)-3-amino- 4-methoxypiperidin-1-yl]-3,4-dihydro-2H-1- benzopyran-3-yl]-4,6-dimethylthieno[2,3- b]pyridine-2-carboxamide

319. 7-amino-N-[(2S)-6-[(3S,4S)-3-amino-4- (propan-2-yloxy)pyrrolidin-1-yl]-1,2,3,4- tetrahydronaphthalen-2-yl]-3- methylthieno[2,3-b]pyrazine-6-carboxamide

320. 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4- (propan-2-yloxy)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

321. 3-amino-N-[(6S)-2-[(3S,4R)-3-amino- 4-(propan-2-yloxy)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

322. 3-amino-N-[(6S)-2-[(3R,4S)-3-amino- 4-(propan-2-yloxy)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

323. 3-amino-N-[(3R)-7-[(3S,4R)-3-amino- 4-ethoxpyrrolidin-1-yl]-3,4-dihydro-2H-1- benzopyran-3-yl]-4,6-dimethylthieno[2,3- b]pyridine-2-carboxamide

324. 3-amino-N-[(3R)-7-[(3R,4S)-3-amino- 4-ethoxypyrrolidin-1-yl]-3,4-dihydro-2H-1- benzopyran-3-yl]-4,6-dimethylthieno[2,3- b]pyridine-2-carboxamide

325. 3-amino-N-[(3R)-7-[(3S,4S)-4-amino- 3-methoxy-3-methylpyrrolidin-1-yl]- 2H,3H,4H-pyrano[2,3-b]pyridin-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

326. 3-amino-N-[(3R)-7-[(3R,4R)-4-amino- 3-methoxy-3-methylpyrrolidin-1-yl]- 2H,3H,4H-pyrano[2,3-b]pyridin-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

327. 3-amino-N-[(6S)-2-[(3R,4S)-3-amino- 4-(methoxymethyl)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

328. 3-amino-N-[(6S)-2-[(3S,4R)-3-amino- 4-(methoxymethyl)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

329. N-[(6S)-2-[(4aS,7aS)-4,4-difluoro- octahydro-1H-pyrrolo[3,4-b]pyridin-6-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

330. N-[(6S)-2-[(4aR,7aR)-4,4-difluoro- octahydro-1H-pyrrolo[3,4-b]pyridin-6-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

331. 3-amino-N-[(6S)-2-[(3R,4S)-3-hydroxy- 3-methyl-4-(methylamino)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

332. 3-amino-N-[(6S)-2-[(3S,4R)-3-hydroxy- 3-methyl-4-(methylamino)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

333. 3-amino-N-[(3R)-7-[(2S,3S,4S)-3- amino-4-methoxy-2-methylpyrrolidin-1-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

334. 3-amino-N-[(3R)-7-[(2S,3S,4R)-4- amino-3-methoxy-2-methylpyrrolidin-1-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

335. 3-amino-N-[(3R)-7-[(2R,3R,4R)-3- amino-4-methoxy-2-methylpyrrolidin-1-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

336. 3-amino-N-[(3R)-7-[(2R,3R,4S)-4- amino-3-methoxy-2-methylpyrrolidin-1-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

337. 3-amino-N-[(3R)-7-[(8R)-8-amino-5- oxa-2-azaspiro[3.4]octan-2-yl]-3,4-dihydro- 2H-1-benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

338. 3-amino-N-[(3R)-7-[(8S)-8-amino-5- oxa-2-azaspiro[3.4]octan-2-yl]-3,4-dihydro- 2H-1-benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

339. 3-amino-N-[(3R)-7-[(4R,8R)-8-amino- 1-oxa-6-azaspiro[3.4]octan-6-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

340. 3-amino-N-[(3R)-7-[(4S,8S)-8-amino- 1-oxa-6-azaspiro[3.4]octan-6-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

341. 3-amino-N-[(6S)-2-[(3S,4R)-4-amino- 3-(methoxymethyl)-3-methylpyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

342. 3-amino-N-[(6S)-2-[(3R,4R)-4-amino- 3-(methoxymethyl)-3-methylpyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

343. 3-amino-N-[(6S)-2-[(3S,4S)-4-amino-3- (methoxymethyl)-3-methylpyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

344. 3-amino-N-[(6S)-2-[(3R,4S)-4-amino- 3-(methoxymethyl)-3-methylpyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

345. 3-amino-N-[(6S)-2-[(3R,4R)-3-amino- 4-(difluoromethyl)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

346. 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4- (difluoromethyl)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

347. 3-amino-N-[(6S)-2-[(3R,4S)-3-amino- 4-(difluoromethyl)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

348. 3-amino-N-[(3R)-7-[(3R,4R)-3-amino- 4-(methoxymethyl)pyrrolidin-1-yl]- 2H,3H,4H-pyrano[2,3-b]pyridin-3-yl]-4,6- dimethylthieno[2,3-b]pyridine-2- carboxamide

349. 3-amino-N-[(3R)-7-[(3S,4S)-3-amino- 4-(methoxymethyl)pyrrolidin-1-yl]- 2H,3H,4H-pyrano[2,3-b]pyridin-3-yl]-4,6- dimethylthieno[2,3-b]pyridine-2- carboxamide

350. 3-amino-N-[(3R)-7-[(3S,4S)-3-hydroxy- 4-(methylamino)pyrrolidin-1-yl]-3,4-dihydro- 2H-1-benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

351. 3-amino-N-[(3R)-7-[(7R)-7-amino-2- oxa-5-azaspiro[3.4]octan-5-yl]-3,4-dihydro- 2H-1-benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

352. 3-amino-N-[(3R)-7-[(7S)-7-amino-2- oxa-5-azaspiro[3.4]octan-5-yl]-3,4-dihydro- 2H-1-benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

353. N-[(6S)-2-[(3S,4S)-3-amino-4- methoxypyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5-carboxamide

354. 3-amino-N-[(6S)-2-{3,8- diazabicyclo[3.2.1]octan-3-yl}-5,6,7,8- tetrahydroquinolin-6-yl]-4,6- dimethylthieno[2,3-b]pyridine-2- carboxamide

355. 5-chloro-N-[(3R)-7-{3,8- diazabicyclo[3.2.1]octan-3-yl}-5,8-difluoro- 3,4-dihydro-2H-1-benzopyran-3-yl]-7-ethyl- 7H-pyrrolo[2,3-c]pyridazine-3-carboxamide

356. 5-chloro-N-[(3R)-8-cyano-7-{3,8- diazabicyclo[3.2.1]octan-3-yl}-5-fluoro-3,4- dihydro-2H-1-benzopyran-3-yl]-7-ethyl-7H- pyrrolo[2,3-c]pyridazine-3-carboxamide

357. 3-amino-N-[(6S)-2-[(3S,4R)-3-amino- 4-(1,1-difluoroethoxy)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

358. 3-amino-N-[(6S)-2-[(3R,4S)-3-amino- 4-(1,1-difluoroethoxy)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

359. (6aS,7aR)-N-[(2S)-6-{3,8- diazabicyclo[3.2.1]octan-3-yl}-5- (difluoromethyl)-8-fluoro-1,2,3,4- tetrahydronaphthalen-2-yl]- 5H,6H,6aH,7H,7aH-cyclopropa[c]1,8- naphthyridine-2-carboxamide

360. (6aR,7aS)-N-[(2S)-6-{3,8- diazabicyclo[3.2.1]octan-3-yl}-5- (difluoromethyl)-8-fluoro-1,2,3,4- tetrahydronaphthalen-2-yl]- 5H,6H,6aH,7H,7aH-cyclopropa[c]1,8- naphthyridine-2-carboxamide

361. (6aS,7aR)-N-[(2R)-6-{3,8- diazabicyclo[3.2.1]octan-3-yl}-5- (difluoromethyl)-8-fluoro-1,2,3,4- tetrahydronaphthalen-2-yl]- 5H,6H,6aH,7H,7aH-cyclopropa[c]1,8- naphthyridine-2-carboxamide

362. (6aR,7aS)-N-[(2R)-6-{3,8- diazabicyclo[3.2.1]octan-3-yl}-5- (difluoromethyl)-8-fluoro-1,2,3,4- tetrahydronaphthalen-2-yl]- 5H,6H,6aH,7H,7aH-cyclopropa[c]1,8- naphthyridine-2-carboxamide

363. 3-amino-N-[(6S)-2-[(3R,4S)-3-amino- 4-(trifluoromethyl)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

364. 3-amino-N-[(6S)-2-[(3S,4R)-3-amino- 4-(trifluoromethyl)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

365. 7-amino-N-[(6S)-2-[(8R)-8-amino-2- oxa-6-azaspiro[3.4]octan-6-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-3-methylthieno[2,3- b]pyrazine-6-carboxamide

366. 7-amino-N-[(6S)-2-[(8S)-8-amino-2- oxa-6-azaspiro[3.4]octan-6-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-3-methylthieno[2,3- b]pyrazine-6-carboxamide

367. 3-amino-N-[(6S)-2-[(1R,5S)-9,9- difluoro-2,7-diazabicyclo[3.3.1]nonan-7-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

368. 3-amino-N-[(6S)-2-[(1S,5R)-9,9- difluoro-2,7-diazabicyclo[3.3.1]nonan-7-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

369. 3-amino-N-[(3R)-7-[(3S)-3- aminopyrrolidin-1-yl]-3,4-dihydro-2H-1- benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

370. N-[(6S)-2-[(3R,4S)-3-amino-4- (difluoromethyl)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5-carboxamide

371. N-[(6S)-2-[(3S,4R)-3-amino-4- (difluoromethyl)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5-carboxamide

372. 3-amino-N-[(6S)-2-[(3R,4S)-3- (difluoromethyl)-4-acetamidopyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

373. 3-amino-N-[(3R)-7-[3-amino-3- (methoxymethyl)azetidin-1-yl]-3,4-dihydro- 2H-1-benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

374. 3-amino-N-[(6S)-2-[(3S)-3- (difluoromethyl)piperazin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

375. 3-amino-N-[(6S)-2-[(3R)-3- (difluoromethyl)piperazin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

376. 3-amino-N-[(6S)-2-[(3S,4R)-3- (difluoromethyl)-4-(methylamino)pyrrolidin- 1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

377. 3-amino-N-[(6S)-2-[(3R,4S)-3- (difluoromethyl)-4-(methylamino)pyrrolidin- 1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

378. 3-amino-N-[(3R)-7-[(3R,4S)-3-amino- 4-(difluoromethyl)pyrrolidin-1-yl]-2H,3H,4H- pyrano[2,3-b]pyridin-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

379. 3-amino-N-[(3R)-7-[(3S,4R)-3-amino- 4-(difluoromethyl)pyrrolidin-1-yl]-2H,3H,4H- pyrano[2,3-b]pyridin-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

380. 3-amino-N-[(6S)-2-[(3R,4S)-3-amino- 4-(difluoromethyl)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinazolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

381. 3-amino-N-[(6S)-2-[(3S,4R)-3-amino- 4-(difluoromethyl)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinazolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

382. 3-amino-N-[(6R)-2-[(3S,4R)-3-amino- 4-(difluoromethyl)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinazolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

383. 3-amino-N-[(6R)-2-[(3R,4S)-3-amino- 4-(difluoromethyl)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinazolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

384. 3-amino-N-[(6S)-2-[(3R,4S)-3-amino- 4-(fluoromethyl)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

385. 3-amino-N-[(6S)-2-[(3S,4R)-3-amino- 4-(fluoromethyl)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

386. 3-amino-N-[(6S)-2-[(3R)-3-amino-3- (hydroxymethyl)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

387. 3-amino-N-[(6S)-2-[(3S)-3-amino-3- (hydroxymethyl)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

388. 3-amino-N-[(6S)-2-[(3R)-3-amino-3- (methoxymethyl)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

389. 3-amino-N-[(6S)-2-[(3S)-3-amino-3- (methoxymethyl)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

390. 3-amino-N-[(6S)-2-[(5S,9S)-9-amino-1- oxa-7-azaspiro[4.4]nonan-7-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

391. 3-amino-N-[(6S)-2-[(5S,9R)-9-amino- 1-oxa-7-azaspiro[4.4]nonan-7-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

392. 3-amino-N-[(6S)-2-[(5R,9R)-9-amino- 1-oxa-7-azaspiro[4.4]nonan-7-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

393. 3-amino-N-[(6S)-2-[(5R,9S)-9-amino- 1-oxa-7-azaspiro[4.4]nonan-7-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

394. N-[(6S)-2-[(3aR,6aS)-3a-amino- hexahydro-1H-furo[3,4-c]pyrrol-5-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

395. N-[(6S)-2-[(3aS,6aR)-3a-amino- hexahydro-1H-furo[3,4-c]pyrrol-5-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

396. 3-amino-6-methyl-N-[(6S)-2- [(1R,5S,9r)-9-amino-3-oxa-7- azabicyclo[3.3.1]nonan-7-yl]-5,6,7,8- tetrahydroquinolin-6-yl]thieno[2,3- b]pyridine-2-carboxamide

397. 3-amino-6-methyl-N-[(6S)-2- [(1R,5S,9s)-9-amino-3-oxa-7- azabicyclo[3.3.1]nonan-7-yl]-5,6,7,8- tetrahydroquinolin-6-yl]thieno[2,3- b]pyridine-2-carboxamide

398. 3-amino-N-[(6S)-2-[(7R)-7-amino-5- oxa-2-azaspiro[3.4]octan-2-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

399. 3-amino-N-[(6S)-2-[(7S)-7-amino-5- oxa-2-azaspiro[3.4]octan-2-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

400. N-[(6S)-2-[(3R,4R)-3-amino-4- (methoxymethyl)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5-carboxamide

401. N-[(6S)-2-[(3S,4S)-3-amino-4- (methoxymethyl)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5-carboxamide

402. 1-ethyl-N-[(6S)-2-[(3S,4S)-3-methoxy- 4-(methylamino)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-1H-pyrrolo[2,3- b]pyridine-5-carboxamide

403. N-[(6S)-2-[(8R)-8-amino-2-oxa-6- azaspiro[3.4]octan-6-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5-carboxamide

404. N-[(6S)-2-[(8S)-8-amino-2-oxa-6- azaspiro[3.4]octan-6-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5-carboxamide

405. 3-amino-N-[(6S)-2-[(4R,5S)-4-amino- 1-oxa-7-azaspiro[4.4]nonan-7-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

406. 3-amino-N-[(6S)-2-[(4S,5R)-4-amino- 1-oxa-7-azaspiro[4.4]nonan-7-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

407. 3-amino-N-[(6S)-2-[(4S,5S)-4-amino-1- oxa-7-azaspiro[4.4]nonan-7-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

408. 3-amino-N-[(6S)-2-[(4R,5R)-4-amino- 1-oxa-7-azaspiro[4.4]nonan-7-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

409. 3-amino-N-[(3R)-7-[(4R,5S)-4-amino- 1-oxa-7-azaspiro[4.4]nonan-7-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

410. 3-amino-N-[(3R)-7-[(4R,5R)-4-amino- 1-oxa-7-azaspiro[4.4]nonan-7-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

411. 3-amino-N-[(3R)-7-[(4S,5S)-4-amino- 1-oxa-7-azaspiro[4.4]nonan-7-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

412. 3-amino-N-[(3R)-7-[(4S,5R)-4-amino- 1-oxa-7-azaspiro[4.4]nonan-7-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

413. 3-amino-N-[(3R)-5-fluoro-7-[(1R)-1- methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonan- 3-yl]-3,4-dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

414. 3-amino-N-[(3R)-5-fluoro-7-[(1S)-1- methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonan- 3-yl]-3,4-dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

415. 3-amino-N-[(3R)-7-[(3R,4R)-3-amino- 4-methoxypyrrolidin-1-yl]-5,6-difluoro-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

416. 3-amino-N-[(3R)-7-[(3S,4S)-3-amino- 4-methoxpyrrolidin-1-yl]-5,6-difluoro-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

417. 3-amino-N-[(2S)-7,8-difluoro-6- (piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

418. 3-amino-N-[(2R)-7,8-difluoro-6- (piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

419. 3-amino-N-[(6S)-2-[(2R,3R)-3-amino- 2-(methoxymethyl)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

420. 3-amino-N-[(6S)-2-[(2S,3S)-3-amino-2- (methoxymethyl)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

421. N-[(6S)-2-[(3R,4S)-3-amino-4- (trifluoromethyl)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5-carboxamide

422. N-[(6S)-2-[(3S,4R)-3-amino-4- (trifluoromethyl)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5-carboxamide

423. 3-amino-N-[(3R)-7-[(3R,4R)-3-amino- 4-(fluoromethyl)pyrrolidin-1-yl]-3,4-dihydro- 2H-1-benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

424. 3-amino-N-[(3R)-7-[(3S,4S)-3-amino- 4-(fluoromethyl)pyrrolidin-1-yl]-3,4-dihydro- 2H-1-benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

425. N-[(3R)-7-[(3aS,6R,6aS)-6-amino- hexahydro-2H-furo[3,2-b]pyrrol-4-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

426. N-[(3R)-7-[(3aR,6S,6aR)-6-amino- hexahydro-2H-furo[3,2-b]pyrrol-4-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

427. 3-amino-N-[(6S)-2-[(3R,4S)-4-amino- 3-methoxy-3-methylpyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

428. 3-amino-N-[(6S)-2-[(3S,4R)-4-amino- 3-methoxy-3-methylpyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

429. 3-amino-N-[(6S)-2-{7-amino-3,3-dioxo- 3λ⁶-thia-9-azabicyclo[3.3.1]nonan-9-yl}- 5,6,7,8-tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

430. 3-amino-N-[(6S)-2-[(5S,9R)-9-amino- 2-oxa-7-azaspiro[4.4]nonan-7-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

431. 3-amino-N-[(6S)-2-[(5R,9S)-9-amino- 2-oxa-7-azaspiro[4.4]nonan-7-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

432. 3-amino-N-[(3R)-7-[(5S,9S)-9-amino- 2-oxa-7-azaspiro[4.4]nonan-7-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

433. 3-amino-N-[(3R)-7-[(5R,9S)-9-amino- 2-oxa-7-azaspiro[4.4]nonan-7-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

434. N-[(6S)-2-[(3aR,6aS)-3a-methoxy- octahydropyrrolo[2,3-c]pyrrol-5-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

435. N-[(6S)-2-[(3aS,6aR)-3a-methoxy- octahydropyrrolo[2,3-c]pyrrol-5-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

436. 3-amino-N-[(2S)-6-[(3R,4R)-3-amino- 4-(fluoromethyl)pyrrolidin-1-yl]-1,2,3,4- tetrahydronaphthalen-2-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

437. 3-amino-N-[(6S)-2-[(5R,9R)-9-amino- 2-oxa-7-azaspiro[4.4]nonan-7-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

438. 3-amino-N-[(6S)-2-[(5S,9S)-9-amino-2- oxa-7-azaspiro[4.4]nonan-7-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide

439. 3-amino-N-[(3R)-7-[(5R,9R)-9-amino- 2-oxa-7-azaspiro[4.4]nonan-7-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

440. 3-amino-N-[(3R)-7-[(5S,9R)-9-amino- 2-oxa-7-azaspiro[4.4]nonan-7-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

441. 3-amino-N-[(6S)-2-[(3R,4R)-3- (fluoromethyl)-4-(methylamino)pyrrolidin-1- yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

442. 3-amino-N-[(6S)-2-[(3S,4S)-3- (fluoromethyl)-4-(methylamino)pyrrolidin-1- yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

443. 3-amino-N-[(3R)-7-[(3R,4R)-3- (fluoromethyl)-4-(methylamino)pyrrolidin-1- yl]-3,4-dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

444. 3-amino-N-[(3R)-7-[(3S,4S)-3- (fluoromethyl)-4-(methylamino)pyrrolidin-1- yl]-3,4-dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

445. 3-amino-N-[(6R)-2-[(3R,4R)-3-amino- 4-(fluoromethyl)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinazolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

446. 3-amino-N-[(6R)-2-[(3S,4S)-3-amino- 4-(fluoromethyl)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinazolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

447. 3-amino-N-[(2S)-6-[(3S,4S)-3-amino-4- (fluoromethyl)pyrrolidin-1-yl]-1,2,3,4- tetrahydronaphthalen-2-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide

448. N-((2S)-6-(9-oxa-3,7- diazabicyclo[3.3.1]nonan-3-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-7-amino-3- methylthieno[2,3-b]pyrazine-6-carboxamide

449. N-((2S)-6-(9-oxa-3,7- diazabicyclo[3.3.1]nonan-3-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

450. N-((2R)-6-(9-oxa-3,7- diazabicyclo[3.3.1]nonan-3-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-7-amino-3- methylthieno[2,3-b]pyrazine-6-carboxamide

451. N-((2R)-6-(9-oxa-3,7- diazabicyclo[3.3.1]nonan-3-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide

452. (R)-N-(6-(1,4-diazepan-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-7-amino-3- methylthieno[2,3-b]pyrazine-6-carboxamide

453. 7-amino-N-((R)-6-((S)-6-fluoro-1,4- diazepan-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-3- methylthieno[2,3-b]pyrazine-6-carboxamide

454. (S)-7-amino-N-(6-(6,6-difluoro-1,4- diazepan-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-3- methylthieno[2,3-b]pyrazine-6-carboxamide

455. (S)-N-(6-(1,4-diazepan-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-7-amino-3- methylthieno[2,3-b]pyrazine-6-carboxamide

456. N-((2S)-6-(3-oxa-7,9- diazabicyclo[3.3.1]nonan-7-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-7-amino-3- methylthieno[2,3-b]pyrazine-6-carboxamide

457. (R)-7-bromo-N-(7-(piperazin-1- yl)chroman-3-yl)pyrazolo[1,5-a]pyridine-3- carboxamide

458. (R)-7-methyl-N-(7-(piperazin-1- yl)chroman-3-yl)pyrazolo[1,5-a]pyridine-3- carboxamide

459. (R)-1-acetyl-N-(7-(piperazin-1- yl)chroman-3-yl)-1,2,3,4- tetrahydroquinoline-6-carboxamide

460. (R)-N-(7-(piperazin-1-yl)chroman-3- yl)pyrazolo[1,5-a]pyridine-3-carboxamide

461. (R)-5-methoxy-N-(7-(piperazin-1- yl)chroman-3-yl)pyrazolo[1,5-a]pyridine-3- carboxamide

462. (R)-6-chloro-N-(7-(piperazin-1- yl)chroman-3-yl)pyrazolo[1,5-a]pyridine-3- carboxamide

463. (R)-5,7-dimethyl-N-(7-(piperazin-1- yl)chroman-3-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide

464. (R)-6-chloro-N-(7-(piperazin-1- yl)chroman-3-yl)imidazo[1,2-b]pyridazine-2- carboxamide

465. (R)-5-methyl-N-(7-(piperazin-1- yl)chroman-3-yl)pyrazolo[1,5-a]pyridine-3- carboxamide

466. (R)-N-(7-(piperazin-1-yl)chroman-3- yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

467. (R)-6-((3-chlorobenzyl)amino)-N-(7- (piperazin-1-yl)chroman-3-yl)nicotinamide

468. (R)-N-(7-(piperazin-1-yl)chroman-3-yl)- 6-((pyridin-3-ylmethyl)amino)nicotinamide

469. (R)-N-(7-(piperazin-1-yl)chroman-3-yl)- 6-((3- (trifluoromethyl)benzyl)amino)nicotinamide

470. (R)-N-(7-(piperazin-1-yl)chroman-3-yl)- 6-((pyridin-2-ylmethyl)amino)nicotinamide

471. (R)-6-(((2,3- dihydrobenzo[b][1,4]dioxin-6- yl)methyl)amino)-N-(7-(piperazin-1- yl)chroman-3-yl)nicotinamide

472. (R)-6-(((2,3-dihydrobenzofuran-5- yl)methyl)amino)-N-(7-(piperazin-1- yl)chroman-3-yl)nicotinamide

473. (R)-6-((3-acetamidobenzyl)amino)-N- (7-(piperazin-1-yl)chroman-3- yl)nicotinamide

474. 7-ethyl-N-[(3R)-7-(piperazin-1-yl)-3,4- dihydro-2H-1-benzopyran-3-yl]pyrazolo[1,5- a]pyridine-3-carboxamide

475. 7-(hydroxymethyl)-N-[(3R)-7- (piperazin-1-yl)-3,4-dihydro-2H-1- benzopyran-3-yl]pyrazolo[1,5-a]pyridine-3- carboxamide

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims. 

What is claimed is:
 1. A compound of Formula (VI)

or a pharmaceutically acceptable salt thereof, wherein: X is chosen from C(R)(R″) and O; each of Y₁, Y₂, and Y₃ is independently chosen from C(R₃) and N; R′ is chosen from H, deuterium, and CH₃; each of R and R″ is independently chosen from H, halogens, —OH, —CN, C₁-C₆ alkyl optionally substituted with one or more Ri, R and R″ together with the carbon they are attached form a spirocyclic cyclopropyl optionally substituted with one or more Ri, wherein any R, R″, or Ri group being or containing hydrogen can independently have one or more hydrogen replaced with deuterium; each Ri is independently chosen from halogen, —OH, and CH₃; R₁ is chosen from 6-12 membered fused and nonfused heteroaryls optionally substituted with one or more substituent chosen from R₅ and/or R₆, and further wherein any R₁ group containing hydrogen can have one or more hydrogen replaced with deuterium; R₂ is chosen from N-linked 4-12 membered heterocyclyls, C-linked 4-12 membered heterocyclyls, and an —O-linked 4-12 membered heterocyclyl, wherein the 4-12 membered heterocyclyls are optionally substituted with one or more R₅ (which can be the same or different from the one or more R₅ of R₁), and further wherein any hydrogen in a R₂ group can have one or more hydrogen replaced with deuterium; each R₃ is independently chosen from H, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —CN, (C₃-C₈) cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups, wherein each of (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted with one or more R₇; R₄ is chosen from H, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —CN, (C₃-C₈) cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups, wherein each of (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, (C₃-C₈) cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R₅, and further wherein any R₄ group containing hydrogen can have one or more hydrogen replaced with deuterium; each R₅ is independently chosen from —OH, —NH₂, amido-(C₁-C₆) alkyl, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, cycloalkyl, heterocycloalkyl, and —C(O)-heterocycloalkyl groups, wherein each of —NH₂, amido-(C₁-C₆) alkyl, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, cycloalkyl, heterocycloalkyl, and —C(O)-heterocycloalkyl are optionally substituted with one or more substituent independently chosen from (C₁-C₆) alkyl, (C₁-C₆) alkoxy, —NH₂, and —OH, and wherein any R₅ group containing hydrogen can have one or more hydrogen replaced with deuterium; each R₆ is independently chosen from -amino alkyl-aryls, -amino alkyl-heteroaryls, -amino alkyl-cyclyl, and -amino alkyl-heterocyclyl groups, wherein each of the R₆ groups are optionally substituted with one or more substituent chosen from —OH, —NH₂, halogens, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, and (C₁-C₆) haloalkyl groups, and further wherein any R₆ group containing hydrogen can have one or more hydrogen replaced with deuterium; each R₇ is independently chosen from —OH, —NH₂, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, cycloalkyl, —C(O)-cycloalkyl, heterocycloalkyl, and —C(O)-heterocycloalkyl groups, wherein each of —NH₂, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, cycloalkyl, —C(O)-cycloalkyl, heterocycloalkyl, and —C(O)-heterocycloalkyl are optionally substituted with one or more substituent independently chosen from (C₁-C₆) alkyl, (C₁-C₆) alkoxy, and —OH; and n is 0, 1, 2, or
 3. 2. The compound of claim 1, of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein each of X, R₁, R₂, R₃, R₇ and n are as defined in Formula (VI); R₄ is chosen from H, (C₁-C₆) alkyl, halogen, and —OH; each R₅ is independently chosen from —OH, —NH₂, —NHC(O)CH₃, —C(O)NHCH₃, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, cycloalkyl, heterocycloalkyl, and —C(O)-heterocycloalkyl groups, wherein each of —NH₂, —NHC(O)CH₃, —C(O)NHCH₃, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, cycloalkyl, heterocycloalkyl, and —C(O)-heterocycloalkyl are optionally substituted with one or more substituent independently chosen from (C₁-C₆) alkyl, (C₁-C₆) alkoxy, —NH₂, and —OH; and each R₆ is independently chosen from —NH(C₁-C₆)alkyl-aryls, —NH(C₁-C₆)alkyl-heteroaryls, —NH(C₁-C₆)alkyl-cyclyl, and —NH(C₁-C₆)alkyl-heterocyclyl groups, wherein each of the R₆ groups are optionally substituted with one or more substituent chosen from —OH, halogens, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, and (C₁-C₆) haloalkyl groups.
 3. The compound of claim 1, of Formula (IIaa):

or a pharmaceutically acceptable salt thereof, wherein R₁ is chosen from 8-9-membered heteroaryls substituted with one or more substituent chosen from R₅ and R₆, wherein each R₅ and R₆ are independently as defined in Formula (II); R₂ is chosen from N-linked 6-12 membered heterocyclyls or C-linked 6-12 membered heterocyclyls optionally substituted with one or more R₅, wherein each R₅ is independently chosen from —OH, —NH₂, —NHC(O)CH₃, —C(O)NHCH₃, (C₁-C₆)alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halagen, cycloalkyl, heterocycloalkyl, and —C(O)-heterocycloalkyl groups, wherein each of —NH₂, —MHC(O)CH₃, —C(O)NHCH₃, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, cycloalkyl, heterocycloalkyl, and —C(O)-heterocycloalkyl are optionally substituted with one or more substituent independently chosen from (C₁-C₆) alkyl, (C₁-C₆) alkoxy, —NH₂, and —OH; and R₃ is independently chosen from H, (C₁-C₆) alkyl, halogen, and —CN, wherein the (C₁-C₆) alkyl groups are optionally substituted with R₇ wherein each R₇ is independently as defined in Formula (VI).
 4. The compound of claim 1, of Formula (IIb′):

or a pharmaceutically acceptable salt thereof, wherein R′ is chosen from H and CH₃; R₁ is chosen from 8-9 membered heteroaryls substituted with one or more substituent chosen from R₅ and R₆, wherein each R₅ and/or R₆ (if present) are independently as defined in Formula (VI); R₂ is chosen from N-linked 6-12 membered heterocyclyls or C-linked 6-12 membered heterocyclyls optionally substituted with one or more R₅, wherein each R₅ is independently as defined in Formula (VI); and R₃ is independently chosen from H, (C₁-C₆) alkyl, halogen, and —CN, wherein the (C₁-C₆) alkyl groups are optionally substituted with R₇ wherein each R₇ is independently as defined in Formula (VI).
 5. The compound of any one of claims 1-4, wherein R₁, optionally substituted with R₅ and/or R₆, is chosen from


6. The compound of any one of claims 1-4, wherein R₂, optionally substituted with R₅, is chosen from


7. The compound of any one of claims 1-4, wherein R₁, optionally substituted with R₅ and/or R₆, is chosen from

R₂, optionally substituted with R₅, is chosen from


8. The compound of any one of claims 1-4, wherein R₁, optionally substituted with R₅ and/or R₆, is chosen from

and R₂, optionally substituted with R₅, is chosen from


9. The compound of claim 1, of Formula (VII):

or a pharmaceutically acceptable sa thereof, wherein Y is chosen from C(R₃) and N; R′ is chosen from H, deuterium, and CH₃; R₁ is chosen from 6-11 membered heteroaryls optionally substituted with one or more substituent chosen from R₅ and/or R₆; R₂ is chosen from N-linked 4-12 membered heterocyclyls and C-linked 4-12 membered heterocyclyls, wherein the heterocyclyls are optionally substituted with one or more R₅, and further wherein any R₂ group containing hydrogen can have one or more hydrogen replaced with deuterium; each R₃ is independently chosen from H, deuterium, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, —OH, —CN, wherein each of (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted with one or more R₇; R₄ is chosen from H, (C₁-C₆) alkyl, halogen, —OH, —CN, and further wherein any R₄ group containing hydrogen can have one or more hydrogen replaced with deuterium; each R₅ (if present) is independently chosen from —OH, —NH₂, NHC(O)CH₃, —C(O)NHCH₃, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, cycloalkyl, heterocycloalkyl, and —C(O)-heterocycloalkyl groups, wherein each of —NH₂, —NHC(O)CH₃, —C(O)NHCH₃, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, cycloalkyl, heterocycloalkyl, and —C(O)-heterocycloalkyl are optionally substituted with one or more substituent independently chosen from (C₁-C₆) alkoxy, —NH₂, and —OH, and wherein any R₅ group containing hydrogen can have one or more hydrogen replaced with deuterium; each R₆ (if present) is chosen from —NH(C₁-C₆)alkyl-aryls, —NH(C₁-C₆) alkyl-heteroaryls, —NH(C₁-C₆)alkyl-heterocyclyl groups, and —NH(C₁-C₆) alkyl-heterocyclyl groups, wherein each of the R₆ groups are optionally substituted with one or more substituent chosen from —OH, —NH₂, halogens, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, and (C₁-C₆) haloalkyl groups, and further wherein any R₆ group containing hydrogen can have one or more hydrogen replaced with deuterium; each R₇ is independently chosen from —OH, —NH₂, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, cycloalkyl, —C(O)-cycloalkyl, heterocycloalkyl, and —C(O)-heterocycloalkyl groups, wherein each of —NH₂, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, cycloalkyl, —C(O)-cycloalkyl, heterocycloalkyl, and —C(O)-heterocycloalkyl are optionally substituted with one or more substituent independently chosen from (C₁-C₆) alkyl, (C₁-C₆) alkoxy, and —OH; and n is 0, 1, 2, or
 3. 10. The compound of claim 9, of Formula (IIIaa):

or a pharmaceutically acceptable salt thereof, wherein R₁ is chosen from 8-11 membered heteroaryls optionally substituted with one or more R₅; R₂ is chosen from N-linked 4-12 membered heterocyclyls and C-linked 4-12 membered heterocyclyls, optionally substituted with one or more R₅; each R₅ (if present) is independently chosen from —OH, —NH₂, NHC(O)CH₃, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, cycloalkyl, heterocycloalkyl, and —C(O)-heterocycloalkyl groups, wherein each of —NH₂, —NHC(O)CH₃, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, cycloalkyl, heterocycloalkyl, and —C(O)-heterocycloalkyl are optionally substituted with one or more substituent independently chosen from (C₁-C₆) alkoxy, —NH₂, and —OH; and n is 0, 1, 2, or
 3. 11. The compound of claim 9, of Formula (VIIaa):

or a pharmaceutically acceptable thereof, wherein R₁ is chosen from 8-9 membered heteroaryls optionally substituted with one or more R₅; R₂ is chosen from N-linked 4-12 membered heterocyclyls optionally substituted with one or more R₅; each R₅ (if present) is independently chosen from —OH, —NH₂, NHC(O)CH₃, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, cycloalkyl, heterocycloalkyl, and —C(O)-heterocycloalkyl groups, wherein each of —NH₂, —NHC(O)CH₃, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, cycloalkyl, heterocycloalkyl, and —C(O)-heterocycloalkyl are optionally substituted with one or more substituent independently chosen from (C₁-C₆) alkoxy, —NH₂, and —OH; and n is 0, 1, 2, or
 3. 12. The compound of any one of claim 10 or 11, wherein R₁ is chosen from

wherein B is chosen from a bond or C; Z is chosen from N, S, C(Rii); Rii is chosen from H, CH₃ and R₅; R₂ is chosen from N-linked 5-8 membered heterocyclyls substituted with one to three R₅; each R₅ (if present) is independently chosen from —OH, —NH₂, NHC(O)CH₃, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, cycloalkyl, heterocycloalkyl, and —C(O)-heterocycloalkyl groups, wherein each of —NH₂, —NHC(O)CH₃, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, cycloalkyl, heterocycloalkyl, and —C(O)-heterocycloalkyl are optionally substituted with one or more substituent independently chosen from (C₁-C₆) alkoxy, —NH₂, and —OH; and n is 0, 1, 2, or
 3. 13. The compound of any one of claims 9-11 wherein R₁, optionally substituted with R₅, is chosen from

and R₂, optionally substituted with R₅, is chosen from


14. The compound claim 1, chosen from any of the following compounds

 1-1: (R)-3-amino-6-methyl-N-(7-(piperazin-1-yl)chroman-3-yl)thieno[2,3- b]pyridine-2-carboxamide;  1-2: (S)-3-amino-6-methyl-N-(7-(piperazin-1-yl)chroman-3-yl)thieno[2,3- b]pyridine-2-carboxamide;  1-3: N-((3R)-7-(3,8-diazabicyclo[3.2.1]octan-3-yl)chroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide;  1-4: N-((3S)-7-(3,8-diazabicyclo[3.2.1]octan-3-yl)chroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide;  1-5: N-((3R)-7-(3,9-diazabicyclo[3.3.1]nonan-3-yl)chroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide;  1-6: N-((3S)-7-(3,9-diazabicyclo[3.3.1]nonan-3-yl)chroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide;  1-7: 3-amino-N-((R)-7-((2R,3S)-2,3-dimethylpiperazin-1-yl)chroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide;  1-8: 3-amino-N-((S)-7-((2R,3S)-2,3-dimethylpiperazin-1-yl)chroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide;  1-9: 3-amino-N-((R)-7-((2S,3R)-2,3-dimethylpiperazin-1-yl)chroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide;  1-10:  3-amino-N-((S)-7-((2S,3R)-2,3-dimethylpiperazin-1-yl)chroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide;  1-11: 3-amino-N-((R)-7-((2R,3R)-2,3-dimethylpiperazin-1-yl)chroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide;  1-12: 3-amino-N-((S)-7-((2R,3R)-2,3-dimethylpiperazin-1-yl)chroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide;  1-13: 3-amino-N-((R)-7-((2S,3S)-2,3-dimethylpiperazin-1-yl)chroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide;  1-14: 3-amino-N-((S)-7-((2S,3S)-2,3-dimethylpiperazin-1-yl)chroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide;  1-15: (R)-3-amino-5-fluoro-6-methyl-N-(7-piperazin-1-yl)chroman-3- yl)thieno[2,3-b]pyridine-2-carboxamide;  1-16: (S)-3-amino-5-fluoro-6-methyl-N-(7-piperazin-1-yl)chroman-3- yl)thieno[2,3-b]pyridine-2-carboxamide;  1-17: N-((3R)-7-(3,8-diazabicyclo[3.2.1]octan-3-yl)chroman-3-yl)-3-amino-5- fluorothieno[2,3-b]pyridine-2-carboxamide;  1-18: N-((3S)-7-(3,8-diazabicyclo[3.2.1]octan-3-yl)chroman-3-yl)-3-amino-5- fluorothieno[2,3-b]pyridine-2-carboxamide;  1-19: N-((3R)-7-(3,8-diazabicyclo[3.2.1]octan-3-yl)chroman-3-yl)-7-amino-3- methylthieno[2,3-b]pyrazine-6-carboxamide;  1-20: N-((3S)-7-(3,8-diazabicyclo[3.2.1]octan-3-yl)chroman-3-yl)-7-amino-3- methylthieno[2,3-b]pyrazine-6-carboxamide;  1-21: (R)-7-amino-3-methyl-N-(7-(piperazin-1-yl)chroman-3-yl)thieno[2,3- b]pyrazine-6-carboxamide;  1-22: (S)-7-amino-3-methyl-N-(7-(piperazin-1-yl)chroman-3-yl)thieno[2,3- b]pyrazine-6-carboxamide;  1-23: N-((3R)-7-(3,8-diazabicyclo[3.2.1]octan-3-yl)chroman-3-yl)-6-amino-2- methylthieno[2,3-d]thiazole-5-carboxamide;  1-24: N-((3S)-7-(3,8-diazabicyclo[3.2.1]octan-3-yl)chroman-3-yl)-6-amino-2- methylthieno[2,3-d]thiazole-5-carboxamide;  1-25: (R)-6-amino-6-methyl-N-(7-(piperazin-1-yl)chroman-3-yl)thieno[2,3- d]thiazole-5-carboxamide;  1-26: (S)-6-amino-6-methyl-N-(7-(piperazin-1-yl)chroman-3-yl)thieno[2,3- d]thiazole-5-carboxamide;  1-27: N-((3S)-7-(3,8-diazabicyclo[3.2.1]octan-3-yl)chroman-3-yl)-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5-carboxamide;  1-28: N-((3R)-7-(3,8-diazabicyclo[3.2.1]octan-3-yl)chroman-3-yl)-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5-carboxamide;  1-29: N-((3R)-7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluorochroman-3-yl)-3- amino-6-methylthieno[2,3-b]pyridine-2-carboxamide;  1-30: N-((3S)-7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluorochroman-3-yl)-3- amino-6-methylthieno[2,3-b]pyridine-2-carboxamide;  1-31: (R)-3-amino-6-methyl-N-(7-(piperazin-1-yl)-6- (trifluoromethoxy)chroman-3-yl)thieno[2,3-b]pyridine-2-carboxamide;  1-32: (S)-3-amino-6-methyl-N-(7-(piperazin-1-yl)-6- (trifluoromethoxy)chroman-3-yl)thieno[2,3-b]pyridine-2-carboxamide;  1-33: (R)-3-amino-N-(8-fluoro-7-(piperazin-1-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide;  1-34: (S)-3-amino-N-(8-fluoro-7-(piperazin-1-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide;  1-35: (R)-3-amino-N-(6-fluoro-7-(piperazin-1-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide;  1-36: (S)-3-amino-N-(6-fluoro-7-(piperazin-1-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide;  1-37: (R)-3-amino-N-(5-fluoro-7-(piperazin-1-yl)chroman-3-yl)-2- methylthieno[2,3-d]thiazole-5-carboxamide;  1-38: (S)-3-amino-N-(5-fluoro-7-(piperazin-1-yl)chroman-3-yl)-2- methylthieno[2,3-d]thiazole-5-carboxamide;  1-39: N-((3R)-7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluorochroman-3-yl)-6- amino-2-methylthieno[2,3-d]thiazole-5-carboxamide;  1-40: N-((3S)-7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluorochroman-3-yl)-6- amino-2-methylthieno[2,3-d]thiazole-5-carboxamide;  1-41: N-((3S)-7-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-5-fluorochroman-3-yl)-3- amino-6-methylthieno[2,3-b]pyridine-2-carboxamide;  1-42: N-((3R)-7-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-5-fluorochroman-3-yl)-3- amino-6-methylthieno[2,3-b]pyridine-2-carboxamide;  2-1: 3-amino-N-((3R)-7-(9,9-difluoro-3,7-diazabicyclo[3.3.1]nonan-3- yl)-chroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide;  2-2: N-((3R)-7-(3,6-diazabicyclo[3.1.1]heptan-3-yl)chroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide;  2-3: N-((3S)-7-(3,6-diazabicyclo[3.1.1]heptan-3-yl)chroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide;  2-4: 3-amino-6-methyl-N-((R)-7-((S)-2-methylpiperazin-1-yl)-chroman-3- yl)thieno[2,3-b]pyridine-2-carboxamide;  2-5: 3-amino-6-methyl-N-((R)-7-((R)-2-methylpiperazin-1-yl)-chroman-3- yl)thieno[2,3-b]pyridine-2-carboxamide;  2-6: N-((3R)-7-(3,8-diazabicyclo[3.2.1]octan-8-yl)chroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide;  2-7: (R)-N-(7-(2,5-diazaspiro[3.4]octan-5-yl)chroman-3-yl)-3-amino-6- methylthienol[2,3-b]pyridine-2-carboxamide;  2-8: 3-amino-6-methyl-N-((R)-7-((S)-3-methylpiperazin-1-yl)-chroman-3- yl)thieno[2,3-b]pyridine-2-carboxamide;  2-9: 3-amino-6-methyl-N-((R)-7-((R)-3-methylpiperazin-1-yl)-chroman-3- yl)thieno[2,3-b]pyridine-2-carboxamide;  2-10: (R)-N-(7-(2-oxa-5,8-diazaspiro[3.5]nonan-5-yl)chroman-3-yl)-3-amino-6- methylthienol[2,3-b]pyridine-2-carboxamide;  2-11: N-((3R)-7-(3,6-diazabicyclo[3.1.1]heptan-3-yl)chroman-3-yl)-7-amino-3- methylthieno[2,3-b]pyrazine-6-carboxamide;  2-12: N-((3R)-7-(3-oxa-7,9-diazabicyclo[3.1.1]nonan-7-yl)chroman-3-yl)-7- amino-3-methylthieno[2,3-b]pyrazine-6-carboxamide;  2-13: N-((3R)-7-(9-oxa-3,7-diazabicyclo[3.1.1]nonan-3-yl)chroman-3-yl)-7- amino-3-methylthieno[2,3-b]pyrazine-6-carboxamide;  2-14: N-((3R)-7-(3,6-diazabicyclo[3.1.1]heptan-3-yl)chroman-3-yl)-3-amino-6- fluorothieno[2,3-b]pyridine-2-carboxamide;  2-15: N-((3R)-7-(3,6-diazabicyclo[3.1.1]heptan-3-yl)chroman-3-yl)-3-amino-5- fluoro-6-methylthieno[2,3-b]pyridine-2-carboxamide;  2-16: (R)-3-amino-5-fluoro-6-methoxy-N-(7-(piperazin-1-yl)chroman-3- yl)thieno[2,3-b]pyridine-2-carboxamide;  2-17: (R)-3-amino-4,6-dimethyl-N-(7-(piperazin-1-yl)chroman-3-yl)thieno[2,3- b]pyridine-2-carboxamide;  2-18: N-((3R)-7-(3,6-diazabicyclo[3.1.1]heptan-3-yl)chroman-3-yl)-3-amino- 4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide;  2-19: 3-amino-N-((3R)-7-(9,9-difluoro-3,7-diazabicyclo[3.3.1]nonan-3- yl)chroman-3-yl)-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide;  2-20: N-((3R)-7-(9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl)chroman-3-yl)-3- amino-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide;  2-21: N-((3R)-7-(3,6-diazabicyclo[3.1.1]heptan-3-yl)chroman-3-yl)-3-amino-6- methyl-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxamide;  2-22: 3-amino-N-((3R)-7-(9,9-difluoro-3,7-diazabicyclo[3.1.1]nonan-3- yl)chroman-3-yl)-6-methyl-4-(trifluoromethyl)thieno[2,3-b]pyridine-2- carboxamide;  2-23: N-((3R)-7-(9-oxa-3,7-diazabicyclo[3.1.1]nonan-3-yl)chroman-3-yl)-3- amino-6-methyl-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxamide;  2-24: N-((3R)-7-(3,8-diazabicyclo[3.2.1]octan-3-yl)chroman-3-yl)-2′,3′-dihydro- 1′H-spiro[cyclopropane-1,4′-[1,8]naphthyridine]-6′-carboxamide;  2-25: N-((3R)-7-(3,8-diazabicyclo[3.2.1]octan-3-yl)chroman-3-yl)-6- (benzylamino)nicotinamide;  2-26: N-((3R)-7-(3,6-diazabicyclo[3.1.1]heptan-3-yl)chroman-3-yl)-6-amino-2- methylthieno[2,3-d]thiazole-5-carboxamide;  2-27: N-((3R)-7-(3,9-diazabicyclo[3.3.1]nonan-3-yl)chroman-3-yl)-6-amino-2- methylthieno[2,3-d]thiazole-5-carboxamide;  2-28: 6-amino-N-((3R)-7-(9,9-difluoro-3,7-diazabicyclo[3.3.1]nonan- 3-yl)chroman-3-yl)-2-methylthieno[2,3-d]thiazole-5-carboxamide;  2-29: N-((3R)-7-(3,9-diazabicyclo[3.3.1]nonan-3-yl)chroman-3-yl)-7-ethyl-7H- pyrrolo[2,3-c]pyridazine-3-carboxamide;  2-30: N-((3R)-7-(9,9-difluoro-3,7-diazabicyclo[3.3.1]nonan-3-yl)-chroman-3-yl)- 1-ethyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide;  2-31: (R)-3-amino-N-(8-cyano-5-fluoro-7-(piperazin-1-yl)chroman-3-yl)-4,6- dimethylthieno[2,3-b]pyridine-2-carboxamide;  2-32: (R)-3-amino-N-(6-cyano-5-fluoro-7-(piperazin-1-yl)chroman-3-yl)-4,6- dimethylthieno[2,3-b]pyridine-2-carboxamide;  2-33: 3-amino-N-((3R)-6-cyano-7-(9,9-difluoro-3,7-diazabicyclo[3.3.1]nonan- 3-yl)chroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide;  2-34: (S)-7-amino-3-methyl-N-(7-methyl-6-(piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)thieno[2,3-b]pyrazine-6-carboxamide;  2-35: (R)-7-amino-3-methyl-N-(7-methyl-6-(piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)thieno[2,3-b]pyrazine-6-carboxamide;  2-36: (S)-7-amino-3-methyl-N-(5-methyl-6-(piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)thieno[2,3-b]pyrazine-6-carboxamide;  2-37: (R)-7-amino-3-methyl-N-(5-methyl-6-(piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)thieno[2,3-b]pyrazine-6-carboxamide;  2-38: 3-amino-N-[(3R)-7-[(3S,4S)-3-amino-4-(Á²Há,f)methoxypyrrolidin-1-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide;  3-1: 3-amino-N-((R)-7-((3S,4S)-3-amino-4-methoxypyrrolidin-1-yl)-chroman- 3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide;  3-2: 3-amino-N-((R)-7-((3R,4R)-3-amino-4-methoxypyrrolidin-1-yl)-chroman- 3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide;  3-3: 3-amino-N-((R)-7-((S)-3-amino-3-(trifluoromethyl)piperidin-1- yl)-chroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide;  3-4: 3-amino-N-((R)-7-((R)-3-amino-3-(trifluoromethyl)piperidin-1- yl)-chroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide;  3-5: 3-amino-N-((R)-7-((3R,4S)-3-amino-4-fluoropyrrolidin-1-yl)-chroman-3- yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide;  3-6: 3-amino-N-((R)-7-((3S,4R)-3-amino-4-fluoropyrrolidin-1-yl)-chroman-3- yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide;  3-7: 3-amino-N-((R)-7-((3S,4S)-3-amino-4-fluoropyrrolidin-1-yl)-chroman-3- yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide;  3-8: 3-amino-N-((R)-7-((3S,4R)-3-amino-4-fluoropyrrolidin-1-yl)-chroman-3- yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide;  3-9: 3-amino-N-((R)-7-((3S,4R)-3-amino-4-(trifluoromethoxy)pyrrolidin-1- yl)-chroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide;  3-10: 3-amino-N-((R)-7-((3S,4S)-3-amino-4-(trifluoromethoxy)pyrrolidin-1- yl)-chroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide;  3-11: 3-amino-6-methyl-N-((R)-7-((R)-3-(trifluoromethyl)piperazin-1- yl)-chroman-3-yl)thieno[2,3-b]pyridine-2-carboxamide;  3-12: 3-amino-6-methyl-N-((R)-7-((S)-3-(trifluoromethyl)piperazin-1- yl)-chroman-3-yl)thieno[2,3-b]pyridine-2-carboxamide;  3-13: N-((R)-7-((S)-2,7-diazaspiro[4.5]decan-2-yl)chroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide;  3-14: N-((R)-7-((R)-2,7-diazaspiro[4.5]decan-2-yl)chroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide;  3-15: (1aS,7bR)-N-((3R)-7-(3,8-diazabicyclo[3.2.1]octan-3-yl)chroman-3-yl)- 1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine-6- carboxamide;  3-16: (1aR,7bS)-N-((3R)-7-(3,8-diazabicyclo[3.2.1]octan-3-yl)chroman-3-yl)- 1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine-6- carboxamide;  3-17: 3-amino-N-[(3R)-6,8-difluoro-7-(piperazin-1-yl)-3,4-dihydro-2H-1- benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide;  3-18: 3-amino-N-[(3S)-6,8-difluoro-7-(piperazin-1-yl)-3,4-dihydro-2H-1- benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide;  4-1: (R)-N-(7-oxa-5,8-diazaspiro[3.5]nonan-8-yl)chroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide;  5-1: (R)-3-amino-N-(7-(4,4-difluoropiperidin-1-yl))chroman-3-yl)-3-amino-6- methylthieno[2,3-b]pyridine-2-carboxamide;  5-2: (R)-3-amino-N-(7-(1,1-dioxidothiomorpholino)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide;  5-3: (R)-3-amino-N-(7-(3-hydroxy-3-(trifluoromethyl)azetidin-1-yl)chroman-3- yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide;  5-4: 3-amino-N-((3R)-7-(9,9-difluoro-3-oxa-7-azabicyclo[3.3.1]nonan-7- yl))chroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide;  6-1: (R)-1-(3-(3-amino-6-methylthieno[2,3-b]pyridine-2- carboxamido)chroman-7-yl)piperidine-4-carboxylic acid;  6-2: (R)-1-((R)-3-(3-amino-6-methylthieno[2,3-b]pyridine-2- carboxamido)chroman-7-yl)pyrrolidine-3-carboxylic acid;  6-3: (S)-1-((R)-3-(3-amino-6-methylthieno[2,3-b]pyridine-2- carboxamido)chroman-7-yl)pyrrolidine-3-carboxylic acid;  6-4: (S)-1-(6-(7-amino-3-methylthieno[2,3-b]pyrazine-6-carboxamido)- 5,6,7,8-tetrahydronaphthalen-2-yl)azetidine-3-carboxylic acid;  7-1: (R)-3-amino-N-(7-(4-hydroxypiperidin-1-yl))chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide;  7-2: 3-amino-N-((R)-7-((S)-3-hydroxy-3-methylpiperidin-1-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide;  7-3: 3-amino-N-((R)-7-((R)-3-hydroxy-3-methylpiperidin-1-yl)chroman-3-yl)- 6-methylthieno[2,3-b]pyridine-2-carboxamide;  7-4: 7-amino-N-((S)-6-((R)-6-hydroxy-1,4-diazepan-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-3-methylthieno[2,3-b]pyrazine-6- carboxamide;  7-5: 7-amino-N-((R)-6-((R)-6-hydroxy-1,4-diazepan-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-3-methylthieno[2,3-b]pyrazine-6- carboxamide;  7-6: 7-amino-N-((S)-6-((S)-6-hydroxy-1,4-diazepan-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-3-methylthieno[2,3-b]pyrazine-6- carboxamide;  7-7: 7-amino-N-((R)-6-((S)-6-hydroxy-1,4-diazepan-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-3-methylthieno[2,3-b]pyrazine-6- carboxamide;  7-8: 3-amino-N-((S)-6-((S)-3-(hydroxymethyl)piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-6-methylthieno[2,3-b]pyridine-2- carboxamide;  7-9: 3-amino-N-((S)-6-((R)-3-(hydroxymethyl)piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-6-methylthieno[2,3-b]pyridine-2- carboxamide;  7-10: 3-amino-N-((R)-6-((S)-3-(hydroxymethyl)piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-6-methylthieno[2,3-b]pyridine-2- carboxamide;  7-11: 3-amino-N-((R)-6-((R)-3-(hydroxymethyl)piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-6-methylthieno[2,3-b]pyridine-2- carboxamide;  8-1: (R)-3-amino-N-(7-(4-fluoropiperidin-4-yl))chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide;  9-1: N-((R)-7-(((S)-5-oxa-2-azaspiro[3.4]octan-7-yl)chroman-3-yl)-3- amino-6-methylthieno[2,3-b]pyridine-2-carboxamide;  9-2: N-((R)-7-(((R)-5-oxa-2-azaspiro[3.4]octan-7-yl)chroman-3-yl)-3- amino-6-methylthieno[2,3-b]pyridine-2-carboxamide;   10-1: (R)-3-amino-N-(5-fluoro-7-piperazin-1-yl))chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide;   10-2: 3-amino-N-((R)-7-((3R,4R)-3-amino-4-methoxypyrrolidin-1-yl)-5- fluorochroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide;   10-3: 3-amino-N-((R)-7-((3S,4S)-3-amino-4-methoxypyrrolidin-1-yl)-5- fluorochroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide;   10-4: (R)-3-amino-N-(5-fluoro-7-(piperazin-1-yl-2,2,3,3,5,5,6,6-d8)chroman-3- yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide;   10-5: (S)-3-amino-N-(5-fluoro-7-piperazin-1-yl))chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide;   10-6: N-((3R)-7-(9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl)-5-fluorochroman-3- yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide;   10-7: N-((3R)-7-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-5-fluorochroman-3-yl)-3- amino-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide;  10-8: N-((3R)-7-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-5-fluorochroman-3-yl)-7- amino-3-methylthieno[2,3-b]pyrazine-6-carboxamide;  10-9: (R)-3-amino-N-(5-fluoro-7-(piperazin-1-yl)chroman-3-yl)-4,6- dimethylthieno[2,3-b]pyridine-2-carboxamide;  10-10: (R)-7-amino-N-(5-fluoro-7-(piperazin-1-yl)chroman-3-yl)-3- methylthieno[2,3-b]pyrazine-6-carboxamide;  10-11: (R)-3-amino-N-(5-fluoro-7-(piperazin-1-yl)chroman-3-yl)-6- methoxythieno[2,3-b]pyridine-2-carboxamide;  10-12: N-((3R)-7-(9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl)-5-fluorochroman-3- yl)-7-amino-3-methylthieno[2,3-b]pyrazine-6-carboxamide;  10-13: N-((3R)-7-(9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl)-5-fluorochroman-3- yl)-3-amino-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide;  10-14: (R)-3-amino-N-(5-fluoro-7-(piperazin-1-yl)chroman-3-yl)-6-methyl-4- (trifluoromethyl)thieno[2,3-b]pyridine-2-carboxamide;  10-15: 3-amino-N-[(3R)-5-fluoro-7-(piperazin-1-yl)-3,4-dihydro-2H-1- benzopyran-3-yl]-N,6-dimethylthieno[2,3-b]pyridine-2-carboxamide;  10-16: 3-amino-N-[(3S)-5-fluoro-7-(piperazin-1-yl)-3,4-dihydro-2H-1- benzopyran-3-yl]-N,6-dimethylthieno[2,3-b]pyridine-2-carboxamide;  11-1: N-((2S)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2- carboxamide;  11-2: N-((2R)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2- carboxamide;  11-3: N-((2S)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-3-amino-5-fluoro-6-methylthieno[2,3- b]pyridine-2-carboxamide;  11-4: N-((2R)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-3-amino-5-fluoro-6-methylthieno[2,3- b]pyridine-2-carboxamide;  11-5: N-((2S)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-3-amino-6-methoxythieno[2,3-b]pyridine-2- carboxamide;  11-6: N-((2R)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-3-amino-6-methoxythieno[2,3-b]pyridine-2- carboxamide;  11-7: N-((2S)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-7-amino-3-methylthieno[2,3-b]pyrazine-6- carboxamide;  11-8: N-((2R)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-7-amino-3-methylthieno[2,3-b]pyrazine-6- carboxamide;  11-9: N-((2S)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-1-ethyl-1H-pyrrolo[2,3-b]pyridine-5- carboxamide;  11-10: N-((2R)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-1-ethyl-1H-pyrrolo[2,3-b]pyridine-5- carboxamide;  11-11: (S)-3-amino-N-(8-fluoro-6-(piperazin-1-yl)-1,2,3,4-tetrahydronaphthalen- 2-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide;  11-12: (R)-3-amino-N-(8-fluoro-6-(piperazin-1-yl)-1,2,3,4-tetrahydronaphthalen- 2-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide;  11-13: N-((2S)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-1,2,3,4- tetrahydronaphthalen-2-yl)-7-amino-3-methylthieno[2,3-b]pyrazine-6- carboxamide;  11-14: N-((2R)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-1,2,3,4- tetrahydronaphthalen-2-yl)-7-amino-3-methylthieno[2,3-b]pyrazine-6- carboxamide;  11-15: 3-amino-6-methyl-N-((3R,4R)-4-methyl-7-(piperazin-1-yl)chroman-3- yl)thieno[2,3-b]pyridine-2-carboxamide;  11-16: 3-amino-6-methyl-N-((3R,4S)-4-methyl-7-(piperazin-1-yl)chroman-3- yl)thieno[2,3-b]pyridine-2-carboxamide;  11-17: 3-amino-6-methyl-N-((3S,4S)-4-methyl-7-(piperazin-1-yl)chroman-3- yl)thieno[2,3-b]pyridine-2-carboxamide;  11-18: 3-amino-6-methyl-N-((3S,4R)-4-methyl-7-(piperazin-1-yl)chroman-3- yl)thieno[2,3-b]pyridine-2-carboxamide;  11-19: (S)-7-amino-3-methyl-N-(6-(piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)thieno[2,3-b]pyrazine-6-carboxamide;  11-20: (R)-7-amino-3-methyl-N-(6-(piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)thieno[2,3-b]pyrazine-6-carboxamide;  11-21: (S)-3-amino-6-methyl-N-(6-(piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)thieno[2,3-b]pyridine-2-carboxamide;  11-22: (R)-3-amino-6-methyl-N-(6-(piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)thieno[2,3-b]pyridine-2-carboxamide;  11-23: N-((2R)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-7-ethyl-7H-pyrrolo[2,3-c]pyridazine-3- carboxamide;  11-24: N-((2S)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-7-ethyl-7H-pyrrolo[2,3-c]pyridazine-3- carboxamide;  11-25: 7-amino-3-methyl-N-((S)-6-((S)-3-(methylamino)pyrrolidin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)thieno[2,3-b]pyrazine-6-carboxamide;  11-26: 7-amino-3-methyl-N-((R)-6-((S)-3-(methylamino)pyrrolidin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)thieno[2,3-b]pyrazine-6-carboxamide;  11-27: 7-amino-3-methyl-N-((S)-6-((R)-3-(methylamino)pyrrolidin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)thieno[2,3-b]pyrazine-6-carboxamide;  11-28: 7-amino-3-methyl-N-((R)-6-((R)-3-(methylamino)pyrrolidin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)thieno[2,3-b]pyrazine-6-carboxamide;  11-29: N-((S)-6-(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-7-amino-3-methylthieno[2,3-b]pyrazine-6- carboxamide;  11-30: N-((R)-6-(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-7-amino-3-methylthieno[2,3-b]pyrazine-6- carboxamide;  11-31: N-((S)-6-(1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-7-amino-3-methylthieno[2,3-b]pyrazine-6- carboxamide;  11-32: N-((R)-6-(1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-7-amino-3-methylthieno[2,3-b]pyrazine-6- carboxamide;  11-33: (S)-6-amino-2-methyl-N-(6-(piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)thieno[2,3-d]thiazole-5-carboxamide;  11-34: (R)-6-amino-2-methyl-N-(6-(piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)thieno[2,3-d]thiazole-5-carboxamide;  11-35: N-((2S)-6-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2- carboxamide;  11-36: N-((2R)-6-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2- carboxamide;  11-37: (R)-7-amino-N-(8-fluoro-6-(piperazin-1-yl)-1,2,3,4-tetrahydronaphthalen- 2-yl)-3-methylthieno[2,3-b]pyrazine-6-carboxamide;  11-38: (S)-7-amino-N-(8-fluoro-6-(piperazin-1-yl)-1,2,3,4-tetrahydronaphthalen- 2-yl)-3-methylthieno[2,3-b]pyrazine-6-carboxamide;  11-39: N-((2S)-6-(9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl)-8-fluoro-1,2,3,4- tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2- carboxamide;  11-40: N-((2R)-6-(9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl)-8-fluoro-1,2,3,4- tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2- carboxamide;  12-1: N-((2S)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-6-amino-2-methylthieno[2,3-d]thiazole-5- carboxamide;  12-2: N-((2R)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-6-amino-2-methylthieno[2,3-d]thiazole-5- carboxamide;  13-1: N-((3R)-7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5,8-difluorochroman-3-yl)- 3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide;  13-2: N-((3S)-7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5,8-difluorochroman-3-yl)- 3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide;  13-3: N-((3R)-7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5,6-difluorochroman-3-yl)- 3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide;  13-4: N-((3S)-7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5,8-difluorochroman-3-yl)- 3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide;  13-5: (R)-3-amino-N-(6-chloro-7-(piperazin-1-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide;  13-6: (S)-3-amino-N-(6-chloro-7-(piperazin-1-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide;  13-7: (R)-3-amino-N-(8-chloro-7-(piperazin-1-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide;  13-8: (S)-3-amino-N-(8-chloro-7-(piperazin-1-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide;  14-1: N-((2R)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5-cyano-1,2,3,4- tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2- carboxamide;  14-2: N-((2S)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5-cyano-1,2,3,4- tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2- carboxamide;  14-3: N-((2R)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-cyano-1,2,3,4- tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2- carboxamide;  14-4: N-((2S)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-cyano-1,2,3,4- tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2- carboxamide;  14-5: N-((2R)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5-cyano-1,2,3,4- tetrahydronaphthalen-2-yl)-7-amino-3-methylthieno[2,3-b]pyrazine-6- carboxamide;  14-6: N-((2S)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5-cyano-1,2,3,4- tetrahydronaphthalen-2-yl)-7-amino-3-methylthieno[2,3-b]pyrazine-6- carboxamide;  14-7: N-((2R)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-cyano-1,2,3,4- tetrahydronaphthalen-2-yl)-7-amino-3-methylthieno[2,3-b]pyrazine-6- carboxamide;  14-8: N-((2S)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-cyano-1,2,3,4- tetrahydronaphthalen-2-yl)-7-amino-3-methylthieno[2,3-b]pyrazine-6- carboxamide;  14-9: (R)-3-amino-N-(5-cyano-8-fluoro-6-(piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-6-methylthieno[2,3-b]pyridine-2- carboxamide;  14-10: (S)-3-amino-N-(5-cyano-8-fluoro-6-(piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-6-methylthieno[2,3-b]pyridine-2- carboxamide;  14-11: (R)-7-amino-N-(5-cyano-8-fluoro-6-(piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-6-methylthieno[2,3-b]pyrazine-6- carboxamide;  14-12: (S)-7-amino-N-(5-cyano-8-fluoro-6-(piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-3-methylthieno[2,3-b]pyrazine-6- carboxamide;  14-13: (R)-6-amino-N-(5-cyano-8-fluoro-6-(piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-2-methylthieno[2,3-d]thiazole-5- carboxamide;  14-14: (S)-6-amino-N-(5-cyano-8-fluoro-6-(piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-2-methylthieno[2,3-d]thiazole-5- carboxamide;  14-15: 3-amino-N-[(2S)-5-cyano-8-fluoro-6-{9-oxa-3,7- diazabicyclo[3.3.1]nonan-3-yl}1,2,3,4-tetrahydronaphthalen-2-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide;  14-16: 3-amino-N-[(2R)-5-cyano-8-fluoro-6-{9-oxa-3,7- diazabicyclo[3.3.1]nonan-3-yl}1,2,3,4-tetrahydronaphthalen-2-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide;  14-17: 3-amino-N-[(2S)-5-cyano-6-{3,8-diazabicyclo[3.2.1]octan-3-yl}8-fluoro- 1,2,3,4-tetrahydronaphthalen-2-yl)-6-methylthieno[2,3-b]pyridine-2- carboxamide;  14-18: 3-amino-N-[(2R)-5-cyano-6-{3,8-diazabicyclo[3.2.1]octan-3-yl}8-fluoro- 1,2,3,4-tetrahydronaphthalen-2-yl)-6-methylthieno[2,3-b]pyridine-2- carboxamide;  14-19: 7-amino-N-[(2S)-5-cyano-6-{3,8-diazabicyclo[3.2.1]octan-3-yl}8-fluoro- 1,2,3,4-tetrahydronaphthalen-2-yl]-3-methylthieno[2,3-b]pyrazine-6- carboxamide;  14-20: 7-amino-N-[(2R)-5-cyano-6-{3,8-diazabicyclo[3.2.1]octan-3-yl}8-fluoro- 1,2,3,4-tetrahydronaphthalen-2-yl]-3-methylthieno[2,3-b]pyrazine-6- carboxamide;  14-21: 6-amino-N-[(2S)-5-cyano-6-{3,8-diazabicyclo[3.2.1]octan-3-yl}8-fluoro- 1,2,3,4-tetrahydronaphthalen-2-yl]-2-methylthieno[2,3-d][1.3]thiazole-5- carboxamide;  14-22: 6-amino-N-[(2R)-5-cyano-6-{3,8-diazabicyclo[3.2.1]octan-3-yl}8-fluoro- 1,2,3,4-tetrahydronaphthalen-2-yl]-2-methylthieno[2,3-d][1.3]thiazole-5- carboxamide;  14-23: 3-amino-N-[(2S)-6-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-5-cyano- 8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide;  14-24: 3-amino-N-[(2R)-6-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-5-cyano- 8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide;  15-1: (R)-3-amino-6-methyl-N-(3-(piperazin-1-yl)-5,6,7,8-tetrahydroquinolin-7- yl)thieno[2,3-b]pyridine-2-carboxamide;  15-2: (S)-3-amino-6-methyl-N-(3-(piperazin-1-yl)-5,6,7,8-tetrahydroquinolin-7- yl)thieno[2,3-b]pyridine-2-carboxamide;  16: (R)-3-amino-6-methyl-N-(7-(piperazin-1-yl)-3,4-dihydro-2H-pyrano[3,2- c]pyridin-3-yl)thieno[2,3-b]pyridine-2-carboxamide;  17: N-((3R)-7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3,4-dihydro-2H- pyrano[3,2-c]pyridin-3-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2- carboxamide;  18: N-((3R)-7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-3,4-dihydro-2H- pyrano[3,2-c]pyridin-3-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2- carboxamide;  19: (R)-3-amino-6-methyl-N-(7-(piperazin-1-yl)-3,4-dihydro-2H-pyrano[2,3- b]pyridin-3-yl)thieno[2,3-b]pyridine-2-carboxamide;  20: (R)-3-amino-N-(6-fluoro-7-(piperazin-1-yl)-3,4-dihydro-2H-pyrano[2,3- b]pyridin-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide;  21-1: N-((2R)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-1,2,3,4- tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2- carboxamide;  21-2: N-((2S)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-1,2,3,4- tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2- carboxamide;  21-3: N-((2R)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-fluoro-1,2,3,4- tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2- carboxamide;  21-4: N-((2S)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-fluoro-1,2,3,4- tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2- carboxamide;  21-5: (R)-3-amino-N-(5-fluoro-6-(piperazin-1-yl)-1,2,3,4-tetrahydronaphthalen- 2-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide;  21-6: (S)-3-amino-N-(5-fluoro-6-(piperazin-1-yl)-1,2,3,4-tetrahydronaphthalen- 2-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide;  21-7: (R)-3-amino-N-(7-fluoro-6-(piperazin-1-yl)-1,2,3,4-tetrahydronaphthalen- 2-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide;  21-8: (S)-3-amino-N-(7-fluoro-6-(piperazin-1-yl)-1,2,3,4-tetrahydronaphthalen- 2-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide;  21-9: (S)-7-amino-N-(5-fluoro-6-(piperazin-1-yl)-1,2,3,4-tetrahydronaphthalen- 2-yl)-3-methylthieno[2,3-b]pyrazine-6-carboxamide;  21-10: (R)-7-amino-N-(5-fluoro-6-(piperazin-1-yl)-1,2,3,4-tetrahydronaphthalen- 2-yl)-3-methylthieno[2,3-b]pyrazine-6-carboxamide;  21-11: (S)-7-amino-N-(7-fluoro-6-(piperazin-1-yl)-1,2,3,4-tetrahydronaphthalen- 2-yl)-3-methylthieno[2,3-b]pyrazine-6-carboxamide;  21-12 (R)-7-amino-N-(7-fluoro-6-(piperazin-1-yl)-1,2,3,4-tetrahydronaphthalen- 2-yl)-3-methylthieno[2,3-b]pyrazine-6-carboxamide;  22-1: (S)-3-amino-N-(5,8-difluoro-6-(piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-6-methylthieno[2,3-b]pyridine-2- carboxamide;  22-2: (R)-3-amino-N-(5,8-difluoro-6-(piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl)-6-methylthieno[2,3-b]pyridine-2- carboxamide;  22-3: N-((2S)-6-(9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl)-5,8-difluoro-1,2,3,4- tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2- carboxamide;  22-4: N-((2R)-6-(9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl)-5,8-difluoro-1,2,3,4- tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2- carboxamide;  22-5: 3-amino-N-[(2S)-6-{3,8-diazabicyclo[3.2.1]octan-3-yl}-5,8-difluoro- 1,2,3,4-tetrahydronaphthalen-2-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide;  22-6: 3-amino-N-[(2R)-6-{3,8-diazabicyclo[3.2.1]octan-3-yl}-5,8-difluoro- 1,2,3,4-tetrahydronaphthalen-2-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide;  23-1: 7-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-3-methylthieno[2,3-b]pyrazine-6-carboxamide;  23-2: 7-amino-N-[(6R)-2-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-3-methylthieno[2,3-b]pyrazine-6-carboxamide;  23-3: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-4,6-dimethylthieno[2,3-b]pyridine-2- carboxamide;  23-4: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide;  23-5: 3-amino-N-[(6R)-2-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide;  23-6: 7-amino-3-methyl-N-[(6S)-2-piperazin-1-yl]-5,6,7,8-tetrahydroquinolin- 6-yl]thieno[2,3-b]pyrazine-6-carboxamide;  23-7: 3-amino-6-methyl-N-[(6S)-2-piperazin-1-yl]-5,6,7,8-tetrahydroquinolin- 6-yl]thieno[2,3-b]pyridine-6-carboxamide;  23-8: 3-amino-6-methyl-N-[(6R)-2-piperazin-1-yl]-5,6,7,8-tetrahydroquinolin- 6-yl]thieno[2,3-b]pyridine-2-carboxamide;  23-9: 6-amino-2-methyl-N-[(6S)-2-piperazin-1-yl]-5,6,7,8-tetrahydroquinolin- 6-yl]thieno[2,3-d]thiazole-5-carboxamide;  23-10: 3-amino-N-[(6S)-2-{3,6-diazabicyclo[3.1.1]heptan-3-yl}-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide;  23-11: 7-amino-N-[(6S)-2-{3,6-diazabicyclo[3.1.1]heptan-3-yl}-5,6,7,8- tetrahydroquinolin-6-yl]-3-methylthieno[2,3-b]pyrazine-6-carboxamide;  23-12: 3-amino-N-[(6S)-2-{3,8-diazabicyclo[3.2.1]octan-3-yl}-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide;  23-13: 7-amino-N-[(6S)-2-{3,8-diazabicyclo[3.2.1]octan-3-yl}-5,6,7,8- tetrahydroquinolin-6-yl]-3-methylthieno[2,3-b]pyrazine-6-carboxamide;  23-14: 3-amino-4,6-dimethyl-N-[(6S)-2-piperazin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]thieno[2,3-b]pyridine-2-carboxamide;  23-15: 3-amino-6-methyl-N-[(6S)-2-[(3S)-3-methylpiperazin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]thieno[2,3-b]pyridine-2-carboxamide;  23-16: 3-amino-6-methyl-N-[(6S)-2-[(3R)-3-methylpiperazin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]thieno[2,3-b]pyridine-2-carboxamide;  23-17: 3-amino-N-[(6S)-4-fluoro-2-(piperazin-1-yl)-5,6,7,8-tetrahydroquinolin-6- yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide;  23-18: 3-amino-N-[(6S)-2-{3,8-diazabicyclo[3.2.1]octan-3-yl}4-fluoro-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyrazine-6-carboxamide;  24-1: 3-amino-N-[(6S)-2-[(3R,4R)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide;  24-2: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide;  25: 3-amino-N-[(6S)-2-[(3S,4R)-3-amino-4-(difluoromethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide;  26-1: 3-amino-N-[(6S)-2-[(3S,4R)-3-(methoxymethyl)-4- (methylamino)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide;  26-2: 3-amino-N-[(6S)-2-[(3R,4S)-3-(methoxymethyl)-4- (methylamino)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide;  27-1: 3-amino-N-[(6S)-2-[(3R,4R)-3-amino-4-(fluoromethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide;  27-2: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-(fluoromethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide;  28-1: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-(2-methoxyethoxy)pyrrolidin-1- yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide;  28-2: 3-amino-N-[(6S)-2-[(3R,4R)-3-amino-4-(2-methoxyethoxy)pyrrolidin-1- yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide;  29-1: 3-amino-N-[(6S)-2-[(9S)-9-amino-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide;  29-2: 3-amino-N-[(6S)-2-[(9R)-9-amino-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide;  30-1: 3-amino-N-[(6S)-3-fluoro-2-(piperazin-1-yl)-5,6,7,8-tetrahydroquinolin-6- yl]thieno[2,3-b]pyridine-2-carboxamide;  30-2: 3-amino-N-[(6R)-3-fluoro-2-(piperazin-1-yl)-5,6,7,8-tetrahydroquinolin-6- yl]thieno[2,3-b]pyridine-2-carboxamide;  31-1: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-(propan-2-yloxy)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinazolin-6-yl]-4,6-dimethylthieno[2,3-b]pyridine-2- carboxamide;  31-2: 3-amino-N-[(6R)-2-[(3S,4S)-3-amino-4-(propan-2-yloxy)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinazoolin-6-yl]-4,6-dimethylthieno[2,3-b]pyridine-2- carboxamide;  31-3: 3-amino-6-methyl-N-[(6′S)-2′-(piperazin-1-yl)-6′,7′-dihydro-5′H- spiro[cyclopropane-1-8′-quinoline]-6′-yl]thieno[2,3-b]pyridine-2- carboxamide;  31-4: 3-amino-6-methyl-N-[(6′S)-2′-(piperazin-1-yl)-6′,7′-dihydro-5′H- spiro[cyclopropane-1-8′-quinoline]-6′-yl]thieno[2,3-b]pyridine-2- carboxamide;  32-1: 3-amino-6-methyl-N-[(7S)-3-(piperazin-1-yl)-5,6,7,8- tetrahydroisoquinolin-7-yl]thieno[2,3-b]pyridine-2-carboxamide;  32-2: 3-amino-6-methyl-N-[(7R)-3-(piperazin-1-yl)-5,6,7,8- tetrahydroisoquinolin-7-yl]thieno[2,3-b]pyridine-2-carboxamide;  33-1: 3-amino-N-[(3R)-5-fluoro-7-(piperazin-1-yl)-3,4-dihydro(4,4-Á²Há,,)-2H- 1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide;  33-2: 3-amino-N-[(3S)-5-fluoro-7-(piperazin-1-yl)-3,4-dihydro(4,4-Á²Há,,)-2H- 1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide;  33-3: 3-amino-N-[(3R)-7-{(1R,6S)-3,8-diazabicyclo[4.2.0]octan-8-yl}-3,4- dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide;  33-4: 3-amino-N-[(3R)-7-{(1S,6R)-3,8-diazabicyclo[4.2.0]octan-8-yl}-3,4- dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide;  34: 3-amino-N-[(3R)-7-(4-cyano-1,1-dioxo-1λ6-thian-4-yl)-3,4-dihydro-2H-1- benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide;  35: 3-amino-6-methyl-N-[(3R)-5,6,8-trifluoro-7-(piperazin-1-yl)3,4-dihydro- 2H-1-benzopyran-3-yl]thieno[2,3-b]pyridine-2-carboxamide;  36: (R)-7-amino-2-ethyl-N-(7-(piperazin-1-yl)chroman-3-yl)-thieno[2,3- b]pyrazine-6-carboxamide;  37: (S)-7-amino-2-ethyl-N-(7-(piperazin-1-yl)chroman-3-yl)-thieno[2,3- b]pyrazine-6-carboxamide;  38: (R)-1-(difluoromethyl)-N-(7-(piperazin-1-yl)chroman-3-yl)-1H-pyrrolo[2,3- b]pyridine-5-carboxamide;  39: (S)-1-(difluoromethyl)-N-(7-(piperazin-1-yl)chroman-3-yl)-1H-pyrrolo[2,3- b]pyridine-5-carboxamide;  40: N-((3R)-7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-fluorochroman-3-yl)-7- amino-3-methylthieno[2,3-b]pyrazine-6-carboxamide;  41: N-((3S)-7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-fluorochroman-3-yl)-7- amino-3-methylthieno[2,3-b]pyrazine-6-carboxamide;  42: 3-amino-N-((S)-7-((3aS,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)chroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide;  43: 3-amino-N-((R)-7-((3aR,6aR)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)chroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide;  44: 3-amino-N-((S)-7-((3aR,6aR)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)chroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide;  45: (R)-6-amino-2-cyclopropyl-N-(7-(piperazin-1-yl)chroman-3-yl)-thieno[2,3- d]thiazole-5-carboxamide;  46: N-((3S)-7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-fluorochroman-3-yl)-6- amino-2-methylthieno[2,3-d]thiazole-5-carboxamide;  47: N-((3R)-7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-fluorochroman-3-yl)-6- amino-2-methylthieno[2,3-d]thiazole-5-carboxamide;  48: (R)-3-amino-N-(5-chloro-7-(piperazin-1-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide;  49: (S)-3-amino-N-(5-chloro-7-(piperazin-1-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide;  50: N-((3R)-7-(3,8-diazabicyclo[3.2.1]octan-3-yl)chroman-3-yl)-5,6,7,8- tetrahydro-1,8-naphthyridine-3-carboxamide;  51: N-((3R)-7-(3,8-diazabicyclo[3.2.1]octan-3-yl)chroman-3-yl)-3,4-dihydro- 2H-pyrano[2,3-b]pyridine-2-carboxamide;  52: (R)-6-(benzylamino)-N-(7-(piperazin-1-yl)chroman-3-yl)nicotinamide;  53: 6-(((S)-1-phenylethyl)amino)-N-((R)-7-(piperazin-1-yl)chroman-3- yl)nicotinamide;  54: 6-(((R)-1-phenylethyl)amino)-N-((R)-7-(piperazin-1-yl)chroman-3- yl)nicotinamide;  55: (R)-3-amino-N-(5,8-difluoro-7-(piperazin-1-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide;  56: (R)-6-amino-N-(5,8-difluoro-7-(piperazin-1-yl)chroman-3-yl)-2- methylthieno[2,3-d]thiazole-5-carboxamide;  57: (R)-7-hydroxy-N-((R)-7-(piperazin-1-yl)chroman-3-yl)-6,7-dihydro-5H- cyclopenta[b]pyridine-3-carboxamide;  58: (S)-7-hydroxy-N-((R)-7-(piperazin-1-yl)chroman-3-yl)-6,7-dihydro-5H- cyclopenta[b]pyridine-3-carboxamide;  59: (R)-1-benzyl-N-(7-(piperazin-1-yl)chroman-3-yl)-1H-pyrrolo[2,3- b]pyridine-5-carboxamide;  60: (R)-7-amino-N-(8-cyano-5-fluoro-7-(piperazin-1-yl)chroman-3-yl)-3- methylthieno[2,3-b]pyrazine-6-carboxamide;  61: (R)-3-amino-N-(5,6-difluoro-7-(piperazin-1-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide;  62: 3-amino-N-((R)-7-((3S,4R)-3-hydroxypiperidin-4-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide;  63: 3-amino-N-((R)-7-((3R,4S)-3-hydroxypiperidin-4-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide;  64: 3-amino-N-((R)-7-((3R,4R)-3-hydroxypiperidin-4-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide;  65: 3-amino-N-((R)-7-((3S,4S)-3-hydroxypiperidin-4-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide;  66: (R)-6-amino-N-(5,6-difluoro-7-(piperazin-1-yl)chroman-3-yl)-2- methylthieno[2,3-d]thiazole-5-carboxamide;  67: (R)-7-amino-N-(6-cyano-5-fluoro-7-(piperazin-1-yl)chroman-3-yl)-3- methylthieno[2,3-b]pyrazine-6-carboxamide;  68: (R)-3-amino-N-(5,8-difluoro-7-(piperazin-1-yl)chroman-3-yl)-6- methylfuro[2,3-b]pyridine-2-carboxamide;  69: 3-amino-N-((R)-7-((R)-3,3-difluoropiperidin-4-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide;  70: 3-amino-N-((R)-7-((S)-3,3-difluoropiperidin-4-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide;  71: (R)-7-amino-3-methyl-N-(7-(piperazin-1-yl)-3,4-dihydro-2H-pyrano[3,2- c]pyridin-3-yl)thieno[2,3-b]pyrazine-6-carboxamide;  72: (R)-3-amino-5-fluoro-6-methyl-N-(7-(piperazin-1-yl)-3,4-dihydro-2H- pyrano[3,2-c]pyridin-3-yl)thieno[2,3-b]pyridine-2-carboxamide;  73: (7S)-N-((3R)-7-(3,8-diazabicyclo[3.2.1]octan-3-yl)chroman-3-yl)-7- methyl-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carboxamide;  74: (7R)-N-((3R)-7-(3,8-diazabicyclo[3.2.1]octan-3-yl)chroman-3-yl)-7- methyl-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carboxamide;  75: N-((R)-7-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-3,4-dihydro-2H- pyrano[3,2-c]pyridin-3-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2- carboxamide;  76: N-((R)-7-((1R,4R)-2,5-diazabicyclo[2.2.2]octan-2-yl)-3,4-dihydro-2H- pyrano[3,2-c]pyridin-3-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2- carboxamide;  77: N-((3R)-7-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-8-cyano-5- fluorochroman-3-yl)-7-amino-3-methylthieno[2,3-b]pyrazine-6- carboxamide;  78: N-((3R)-7-(9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl)-5,8- difluorochroman-3-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2- carboxamide;  79: N-((3R)-7-(9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl)-5,6- difluorochroman-3-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2- carboxamide;  80: 3-amino-N-((R)-7-((3R,4R)-3-fluoropiperidin-4-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide;  81: 3-amino-N-((R)-7-((3S,4S)-3-fluoropiperidin-4-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide;  82: 3-amino-N-((R)-7-((3S,4R)-3-fluoropiperidin-4-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide;  83: 3-amino-N-((R)-7-((3R,4S)-3-fluoropiperidin-4-yl)chroman-3-yl)-6- methylthieno[2,3-b]pyridine-2-carboxamide;  84: N-((R)-5,8-difluoro-7-((3R,4S)-3-hydroxypiperidin-4-yl)chroman-3-yl)-7- ethyl-7H-pyrrolo[2,3-c]pyridazine-3-carboxamide;  85: N-((R)-5,8-difluoro-7-((3S,4R)-3-hydroxypiperidin-4-yl)chroman-3-yl)-7- ethyl-7H-pyrrolo[2,3-c]pyridazine-3-carboxamide;  86: 3-amino-N-((R)-7-((3R,4R)-3-amino-4-methoxypyrrolidin-1-yl)-5,8- difluorochroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide;  87: 3-amino-N-((R)-7-((3S,4S)-3-amino-4-methoxypyrrolidin-1-yl)-5,8- difluorochroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide;  88: N-((3R)-7-(9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl)chroman-3-yl)-3- amino-4-(difluoromethyl)-6-methylthieno[2,3-b]pyridine-2-carboxamide;  89: (1aS,7bR)-N-((3R)-7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5,8- difluorochroman-3-yl)-1a,2,3,7b-tetrahydro-1H- cyclopropa[c][1,8]naphthyridine-6-carboxamide;  90: (1aR,7bS)-N-((3R)-7-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5,8- difluorochroman-3-yl)-1a,2,3,7b-tetrahydro-1H- cyclopropa[c][1,8]naphthyridine-6-carboxamide;  91: 3-amino-N-[(3R)-7-[(3R,4R)-3-amino-4-methoxypyrrolidin-1-yl]-8-fluoro- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide;  92: 3-amino-N-[(3R)-7-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-8-fluoro- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide;  93: 3-amino-N-[(3R)-7-[(3R,4R)-3-amino-4-methoxypyrrolidin-1-yl]-6-fluoro- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide;  94: 3-amino-N-[(3R)-7-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-6-fluoro- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide;  95: 3-amino-N-[(3R)-8-cyano-7-{3,8-diazabicyclo[3.2.1]octan-3-yl}-5-fluoro- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide;  96: 3-amino-N-[(3R)-8-cyano-5-fluoro-7-{9-oxa-3,7- diazabicyclo[3.3.1]nonan-3-yl}-3,4-dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide;  97: 7-amino-N-[(3R)-7-{3,8-diazabicyclo[3.2.1]octan-3-yl}-5,6-difluoro-3,4- dihydro-2H-1-benzopyran-3-yl]-3-methylthieno[2,3-b]pyrazine-6- carboxamide;  98: 6-amino-N-[(3R)-7-{3,8-diazabicyclo[3.2.1]octan-3-yl}-5,8-difluoro-3,4- dihydro-2H-1-benzopyran-3-yl]-2-methylthieno[2,3-d]thiazole-5- carboxamide;  99: 3-amino-N-[(2S)-5-fluoro-6-{9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl}- 1,2,3,4-tetrahydronaphthalen-2-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 100: 3-amino-N-[(2R)-5-fluoro-6-{9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl}- 1,2,3,4-tetrahydronaphthalen-2-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 101: 3-amino-N-[(2S)-7-fluoro-6-{9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl}- 1,2,3,4-tetrahydronaphthalen-2-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 102: 3-amino-N-[(2S)-5-fluoro-6-{9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl}- 1,2,3,4-tetrahydronaphthalen-2-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 103: 3-amino-N-[(3R)-7-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-3,4- dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 104: 3-amino-N-[(3R)-7-{3,8-diazabicyclo[3.2.1]octan-3-yl}-6-fluoro-3,4- dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 105: 3-amino-N-[(2R)-8-fluoro-7-{9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl}- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 106: 3-amino-N-[(3R)-6-fluoro-7-{9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl}- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 107: 7-amino-N-[(3R)-7-{3,8-diazabicyclo[3.2.1]octan-3-yl}-5,8-difluoro-3,4- dihydro-2H-1-benzopyran-3-yl]-3-methylthieno[2,3-b]pyrazine-6- carboxamide; 108: 6-amino-N-[(3R)-7-{3,8-diazabicyclo[3.2.1]octan-3-yl}-5,8-difluoro-3,4- dihydro-2H-1-benzopyran-3-yl]-2-methylthieno[2,3-d]thiazole-5- carboxamide; 109: 3-amino-N-[(2S)-7-cyano-6-{9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl}- 1,2,3,4-tetrahydronaphthalen-2-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 110: 3-amino-N-[(3R)-7-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]5,8- difluoro-3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide; 111: 3-amino-N-[(3R)-7-[(1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl]5,8- difluoro-3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide; 112: 3-amino-N-[(3R)-7-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]5,6- difluoro-3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide; 113: 3-amino-N-[(3R)-7-{9,9-difluoro-3,7-diazabicyclo[3.3.1]nonan-2-yl}- 2H,3H,4H-pyrano[2,3-b]pyridin-3-yl)-6-methylthieno[2,3-b]pyridine-2- carboxamide; 114: 3-amino-N-[(3R)-7-{9,9-difluoro-3,7-diazabicyclo[3.3.1]nonan-2-yl}- 2H,3H,4H-pyrano[3,2-c]pyridin-3-yl)-6-methylthieno[2,3-b]pyridine-2- carboxamide; 115: 3-amino-N-[(3R)-7-[(1S,4S)-3-amino-4-ethoxypyrrolidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 116: 3-amino-N-[(2S)-6-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-1,2,3,4- tetrahydronaphthalen-2-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 117: 7-amino-N-[(3R)-7-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-3-methylthieno[2,3-b]pyrazine-6- carboxamide; 118: 6-amino-N-[(3R)-7-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-2-methylthieno[2,3-d]thiazole-5- carboxamide; 119: 3-amino-N-[(3R)-7-[(3S,4S)-3-amino-4-methoxypiperidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 120: 3-amino-N-[(3R)-7-[(3R,4R)-3-amino-4-methoxypiperidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 121: 3-amino-N-[(3R)-7-[(3S,4R)-3-amino-4-methoxypiperidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 122: 3-amino-N-[(3R)-7-[(3R,4S)-3-amino-4-methoxypiperidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 123: 3-amino-6-methyl-N-[(3R)-7-[(1s,4S)-3-aminocyclobutyl]-3,4-dihydro- 2H-1-benzopyran-3-yl]thieno[2,3-b]pyridine-2-carboxamide; 124: 3-amino-6-methyl-N-[(3R)-7-[(1r,3r)-3-aminocyclobutyl]-3,4-dihydro-2H- 1-benzopyran-3-yl]thieno[2,3-b]pyridine-2-carboxamide; 125: 3-amino-6-methyl-N-[(3R)-7-{3-oxa-9-diazabicyclo[3.3.1]nonan-3-yl}-3,4- dihydro-2H-1-benzopyran-3-yl]thieno[2,3-b]pyridine-2-carboxamide; 126: 3-amino-N-[(3R)-6-cyano-7-{3,8-diazabicyclo[3.2.1]octan-3-yl}-5-fluoro- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 127: 3-amino-N-[(3R)-6-cyano-5-fluoro-7-{9-oxa-3,7- diazabicyclo[3.3.1]nonan-3-yl}-3,4-dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide; 128: 3-amino-N-[(3R)-7-[(3S,4S)-4-amino-3-methoxypiperidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 129: 3-amino-N-[(3R)-7-[(3R,4R)-4-amino-3-methoxypiperidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 130: 7-amino-N-[(2S)-6-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-1,2,3,4- tetrahydronaphthalen-2-yl]-3-methylthieno[2,3-b]pyrazine-6- carboxamide; 131: N-[(2S)-6-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-1,2,3,4- tetrahydronaphthalen-2-yl]-7-ethyl-7H-pyrrolo[2,3-c]pyridazine-3- carboxamide; 132: N-[(2S)-6-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-1,2,3,4- tetrahydronaphthalen-2-yl]-1-ethyl-1H-pyrrolo[2,3-b]pyridine-5- carboxamide; 133: 6-amino-N-[(2S)-6-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-1,2,3,4- tetrahydronaphthalen-2-yl]-3-methylthieno[2,3-d][1.3]thiazole-5- carboxamide; 134: 3-amino-N-[(2S)-6-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-1,2,3,4- tetrahydronaphthalen-2-yl]-6-methoxythieno[2,3-b]pyridine-2- carboxamide; 135: 3-amino-N-[(2S)-6-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-1,2,3,4- tetrahydronaphthalen-2-yl]-5-fluoro-6-methoxythieno[2,3-b]pyridine-2- carboxamide; 136: 3-amino-N-[(2S)-6-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-8-fluoro- 1,2,3,4-tetrahydronaphthalen-2-yl]-6-methoxythieno[2,3-b]pyridine-2- carboxamide; 137: 3-amino-N-[(2R)-6-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-8-fluoro- 1,2,3,4-tetrahydronaphthalen-2-yl]-6-methoxythieno[2,3-b]pyridine-2- carboxamide; 138: N-[(2S)-6-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-8-fluoro-1,2,3,4- tetrahydronaphthalen-2-yl]-7-ethyl-7H-pyrrolo[2,3-c]pyridazine-3- carboxamide; 139: N-[(2R)-6-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-8-fluoro-1,2,3,4- tetrahydronaphthalen-2-yl]-7-ethyl-7H-pyrrolo[2,3-c]pyridazine-3- carboxamide; 140: 3-amino-N-[(3R)-7-[(3S,4S)-3-amino-4-cyclopropoxypyrrolidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 141: 3-amino-N-[(3R)-7-[(3S,4S)-3-amino-4-cyclobutoxypyrrolidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 142: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-ethoxypyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide; 143: 3-amino-N-[(2S)-6-[(3S,4R)-3-amino-4-methoxypyrrolidin-1-yl]1,2,3,4- tetrahydronaphthalen-2-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 144: 3-amino-N-[(2S)-6-[(3R,4S)-3-amino-4-methoxypyrrolidin-1-yl]1,2,3,4- tetrahydronaphthalen-2-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 145: 3-amino-N-[(3R)-7-[(3S,4R)-3-amino-4-methoxypyrrolidin-1-yl]-5-fluoro- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 146: 3-amino-N-[(3R)-7-[(3R,4S)-3-amino-4-methoxypyrrolidin-1-yl]-5-fluoro- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 147: 7-amino-N-[(3R)-7-[(3S,4R)-3-amino-4-methoxypyrrolidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-3-methylthieno[2,3-b]pyrazine-6- carboxamide; 148: 7-amino-N-[(3R)-7-[(3R,4S)-3-amino-4-methoxypyrrolidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-3-methylthieno[2,3-b]pyrazine-6- carboxamide; 149: 6-amino-N-[(3R)-7-[(3S,4R)-3-amino-4-methoxypyrrolidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-2-methylthieno[2,3-d]thiazole-5- carboxamide; 150: 6-amino-N-[(3R)-7-[(3R,4S)-3-amino-4-methoxypyrrolidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-2-methylthieno[2,3-d]thiazole-5- carboxamide; 151: 3-amino-N-[(3R)-7-[(3S,4R)-3-amino-4-ethoxypyrrolidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 152: 3-amino-N-[(3R)-7-[(3R,4S)-3-amino-4-ethoxypyrrolidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 153: N-[(3R)-7-[(4aS,7aR)-octahydropyrrolo[3,4-b]morpholin-6-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-3-amino-6-methylthieno[2,3-b]pyridine- 2-carboxamide; 154: N-[(3R)-7-[(4aR,7aS)-octahydropyrrolo[3,4-b]morpholin-6-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-3-amino-6-methylthieno[2,3-b]pyridine- 2-carboxamide; 155: 3-amino-N-[(3R)-7-[(2S)-2-(methoxymethyl)piperazin-1-yl]-3,4-dihydro- 2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 156: 3-amino-N-[(3R)-7-[(2R)-2-(methoxymethyl)piperazin-1-yl]-3,4-dihydro- 2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 157: 3-amino-N-[(3R)-7-[(3R)-3-(methoxymethyl)piperazin-1-yl]-3,4-dihydro- 2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 158: 3-amino-N-[(3R)-7-[(3S)-3-(methoxymethyl)piperazin-1-yl]-3,4-dihydro- 2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 159: 3-amino-N-[(3R)-5,6-difluoro-7-(piperazin-1-yl)-3,4-dihydro-2H-1- benzopyran-3-yl]-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide; 160: 3-amino-N-[(3S)-5,6-difluoro-7-(piperazin-1-yl)-3,4-dihydro-2H-1- benzopyran-3-yl]-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide; 161: 3-amino-N-[(3R)-7-[(3R,4R)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 162: 3-amino-N-[(3R)-7-[(3S,4S)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 163: 3-amino-N-[(3R)-7-[(3S,4R)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 164: 3-amino-N-[(3R)-7-[(3R,4S)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 165: N-[(3R)-7-[(3aR,6aR)-octahydropyrrolo[2,3-c]pyrrolo-1-yl]-3,4-dihydro-2H- 1-benzopyran-3-yl]-3-amino-6-methylthieno[2,3-b]pyridine-2- carboxamide; 166: N-[(3R)-7-[(3aS,6aS)-octahydropyrrolo[2,3-c]pyrrolo-1-yl]-3,4-dihydro-2H- 1-benzopyran-3-yl]-3-amino-6-methylthieno[2,3-b]pyridine-2- carboxamide; 167: 3-amino-N-[(3R)-7-[(3R,4S)-3-amino-4-(difluoromethyl)pyrrolidin-1-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 168: 3-amino-N-[(3R)-7-[(3S,4S)-3-amino-4-(difluoromethyl)pyrrolidin-1-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 169: 3-amino-N-[(3R)-5-fluoro-7-(piperazin-1-yl)-3,4-dihydro-2H-1- benzopyran-3-yl]-6-methylfuro[2,3-b]pyridine-2-carboxamide; 170: 3-amino-N-[(3R)-7-{3,8-diazabicyclo[3.2.1]octan-3-yl}-5-fluoro-3,4- dihydro-2H-1-benzopyran-3-yl]-6-methylfuro[2,3-b]pyridine-2- carboxamide; 171: 3-amino-N-[(2S)-6-{3,8-diazabicyclo[3.2.1]octan-3-yl}-1,2,3,4- tetrahydronaphthalen-2-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 172: 3-amino-N-[(3R)-7-{3,8-diazabicyclo[3.2.1]octan-3-yl}-5,8-difluoro-3,4- dihydro-2H-1-benzopyran-3-yl]-6-methylfuro[2,3-b]pyridine-2- carboxamide; 173: 3-amino-N-[(3R)-7-{3,8-diazabicyclo[3.2.1]octan-3-yl}-2H,3H,4H- pyrano[2,3-b]pyridin-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide; 174: 7-amino-N-[(3R)-7-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-8-cyano- 5-fluoro-3,4-dihydro-2H-1-benzopyran-3-yl]-3-methylthieno[2,3-b]pyrazine-6- carboxamide; 175: 3-amino-N-[(3R)-7-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-8-cyano- 5-fluoro-3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide; 176: 7-amino-N-[(3R)-7-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-6-cyano- 3,4-dihydro-2H-1-benzopyran-3-yl]-3-methylthieno[2,3-b]pyrazine-6- carboxamide; 177: 3-amino-N-[(3R)-7-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-6-cyano- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 178: 3-amino-N-[(2S)-6-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-5-cyano- 1,2,3,4-tetrahydronaphthalen-2-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 179: 3-amino-N-[(3R)-7-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-2H,3H,4H- pyrano[2,3-c]pyridin-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 180: 3-amino-N-[(3R)-7-[(3S,4S)-3-amino-4-ethoxypyrrolidin-1-yl]-2H,3H,4H- pyrano[2,3-c]pyridin-3-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 181: 7-amino-N-[(3R)-7-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]- 2H,3H,4H-pyrano[2,3-b]pyridin-3-yl]-3-methylthieno[2,3-b]pyrazine-6- carboxamide; 182: 7-amino-N-[(3R)-7-[(3S,4S)-3-amino-4-ethoxypyrrolidin-1-yl]-2H,3H,4H- pyrano[2,3-b]pyridin-3-yl]-3-methylthieno[2,3-b]pyrazine-6-carboxamide; 183: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-3-fluoro- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 184: N-[(3R)-7-[(4aR,7aS)-octahydropyrrolo[3,4-b]morpholin-4-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-3-amino-6-methylthieno[2,3-b]pyridine- 2-carboxamide; 185: N-[(3R)-7-[(4aS,7aR)-octahydropyrrolo[3,4-b]morpholin-4-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-3-amino-6-methylthieno[2,3-b]pyridine- 2-carboxamide; 186: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 187: 3-amino-N-[(6R)-2-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 188: N-[(2S)-6-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-1,2,3,4- tetrahydronaphthalen-2-yl]5H,6H,6aH,7H,7aH-cyclopropa[c]1,8- naphthyridine-2-carboxamide; 189: (6aS,7aR)-N-[(2S)-6-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-1,2,3,4- tetrahydronaphthalen-2-yl]5H,6H,6aH,7H,7aH-cyclopropa[c]1,8- naphthyridine-2-carboxamide; 190: (6aR,7aS)-N-[(2S)-6-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-1,2,3,4- tetrahydronaphthalen-2-yl]5H,6H,6aH,7H,7aH-cyclopropa[c]1,8- naphthyridine-2-carboxamide; 191: (6aS,7aR)-N-[(2S)-6-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-1,2,3,4- tetrahydronaphthalen-2-yl]5H,6H,6aH,7H,7aH-cyclopropa[c]1,8- naphthyridine-2-carboxamide; 192: (6aR,7aS)-N-[(2S)-6-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-1,2,3,4- tetrahydronaphthalen-2-yl]5H,6H,6aH,7H,7aH-cyclopropa[c]1,8- naphthyridine-2-carboxamide; 193: (6aS,7aR)-N-[(2R)-6-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-1,2,3,4- tetrahydronaphthalen-2-yl]5H,6H,6aH,7H,7aH-cyclopropa[c]1,8- naphthyridine-2-carboxamide; 194: (6aR,7aS)-N-[(2R)-6-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-1,2,3,4- tetrahydronaphthalen-2-yl]5H,6H,6aH,7H,7aH-cyclopropa[c]1,8- naphthyridine-2-carboxamide; 195: (6aS,7aR)-N-[(2S)-5-cyano-6-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8- fluoro-1,2,3,4-tetrahydronaphthalen-2-yl]5H,6H,6aH,7H,7aH- cyclopropa[c]1,8-naphthyridine-2-carboxamide; 196: (6aR,7aS)-N-[(2S)-5-cyano-6-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8- fluoro-1,2,3,4-tetrahydronaphthalen-2-yl]5H,6H,6aH,7H,7aH- cyclopropa[c]1,8-naphthyridine-2-carboxamide; 197: (6aS,7aR)-N-[(2R)-5-cyano-6-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8- fluoro-1,2,3,4-tetrahydronaphthalen-2-yl]5H,6H,6aH,7H,7aH- cyclopropa[c]1,8-naphthyridine-2-carboxamide; 198: (6aR,7aS)-N-[(2R)-5-cyano-6-{3,8-diazabicyclo[3.2.1]octan-3-yl}-8- fluoro-1,2,3,4-tetrahydronaphthalen-2-yl]5H,6H,6aH,7H,7aH- cyclopropa[c]1,8-naphthyridine-2-carboxamide; 199: 7-amino-N-[(3R)-7-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-6-cyano- 5-fluoro-3,4-dihydro-2H-1-benzopyran-3-yl]-3-methylthieno[2,3- b]pyrazine-6-carboxamide; 200: 3-amino-N-[(3R)-7-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-6-cyano- 5-fluoro-3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide; 201: 3-amino-N-[(2S)-7-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-7-cyano- 1,2,3,4-tetrahydronaphthalen-2-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 202: 3-amino-N-[(3S)-7-[(3S,4S)-3-amino-4-(propan-2-yloxy)pyrrolidin-1-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 203: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-5-fluoro-6-methylthieno[2,3-b]pyridine-2- carboxamide; 204: 3-amino-5-fluoro-6-methyl-N-[(6S)-2-(piperazin-1-yl)-5,6,7,8- tetrahydroquinolin-6-yl]thieno[2,3-b]pyridine-2-carboxamide; 205: 3-amino-6-methyl-N-[(6S,8S)-8-methyl-2-(piperazin-1-yl)-5,6,7,8- tetrahydroquinolin-6-yl]thieno[2,3-b]pyridine-2-carboxamide; 206: 3-amino-6-methyl-N-[(6R,8S)-8-methyl-2-(piperazin-1-yl)-5,6,7,8- tetrahydroquinolin-6-yl]thieno[2,3-b]pyridine-2-carboxamide; 207: 3-amino-6-methyl-N-[(6S,8R)-8-methyl-2-(piperazin-1-yl)-5,6,7,8- tetrahydroquinolin-6-yl]thieno[2,3-b]pyridine-2-carboxamide; 208: 3-amino-6-methyl-N-[(6R,8R)-8-methyl-2-(piperazin-1-yl)-5,6,7,8- tetrahydroquinolin-6-yl]thieno[2,3-b]pyridine-2-carboxamide; 209: 3-amino-6-methyl-N-[(3R)-7-{3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl}- 3,4-dihydro-2H-1-benzopyran-3-yl]thieno[2,3-b]pyridine-2-carboxamide; 210: 3-amino-N-[(6S)-2-[(3S,4S)-4-amino-3-methoxy-3-methylpyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 211: 3-amino-N-[(6S)-2-[(3R,4R)-4-amino-3-methoxy-3-methylpyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 212: 3-amino-N-[(3R)-7-[(3S,4S)-3-methoxy-4-(methylamino)pyrrolidin-1-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 213: 3-amino-N-[(3R)-7-[(3S,4S)-3-acetamido-4-methoxypyrrolidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 214: 3-amino-N-[(3R)-7-[(4R)-4-amino-3,3-dimethylpyrrolidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 215: 3-amino-N-[(3R)-7-[(4S)-4-amino-3,3-dimethylpyrrolidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 216: N-[(6S)-2-[(3aS,6aS)-octahydropyrrolo[2,3-c]pyrrol-1-yl]5,6,7,8- tetrahydroquinolin-6-yl]-3-amino-6-methylthieno[2,3-b]pyridine-2- carboxamide; 217: N-[(6S)-2-[(3aR,6aR)-octahydropyrrolo[2,3-c]pyrrol-1-yl]5,6,7,8- tetrahydroquinolin-6-yl]-3-amino-6-methylthieno[2,3-b]pyridine-2- carboxamide; 218: N-[(6S)-2-[(3aS,6aS)-octahydropyrrolo[2,3-c]pyrrol-1-yl]5,6,7,8- tetrahydroquinolin-6-yl]-3-amino-4,6-dimethylthieno[2,3-b]pyridine-2- carboxamide; 219: N-[(6S)-2-[(3aR,6aR)-octahydropyrrolo[2,3-c]pyrrol-1-yl]5,6,7,8- tetrahydroquinolin-6-yl]-3-amino-4,6-dimethylthieno[2,3-b]pyridine-2- carboxamide; 220: N-[(3R)-7-[(3aS,6aS)-octahydropyrrolo[2,3-c]pyrrol-1-yl]-5-fluoro-3,4- dihydro-2H-1-benzopyran-3-yl]-3-amino-6-methylthieno[2,3-b]pyridine- 2-carboxamide; 221: N-[(3R)-7-[(3aR,6aR)-octahydropyrrolo[2,3-c]pyrrol-1-yl]-5-fluoro-3,4- dihydro-2H-1-benzopyran-3-yl]-3-amino-6-methylthieno[2,3-b]pyridine- 2-carboxamide; 222: N-[(3R)-7-[(3aS,6aS)-octahydropyrrolo[2,3-c]pyrrol-1-yl]-5-fluoro-3,4- dihydro-2H-1-benzopyran-3-yl]-3-amino-4,6-dimethylthieno[2,3- b]pyridine-2-carboxamide; 223: N-[(3R)-7-[(3aR,6aR)-octahydropyrrolo[2,3-c]pyrrol-1-yl]-5-fluoro-3,4- dihydro-2H-1-benzopyran-3-yl]-3-amino-4,6-dimethylthieno[2,3- b]pyridine-2-carboxamide; 224: N-[(3R)-7-[(3aR,7aR)-octahydro-1H-pyrrolo[2,3-c]pyridin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-3-amino-6-methylthieno[2,3-b]pyridine- 2-carboxamide; 225: N-[(3R)-7-[(3aS,7aR)-octahydro-1H-pyrrolo[2,3-c]pyridin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-3-amino-6-methylthieno[2,3-b]pyridine- 2-carboxamide; 226: N-[(3R)-7-[(3aS,6aS)-octahydropyrrolo[2,3-c]pyrrol-1-yl]-3,4-dihydro-2H- 1-benzopyran-3-yl]-3-amino-4,6-dimethylthieno[2,3-b]pyridine-2- carboxamide; 227: N-[(3R)-7-[(3aR,6aR)-octahydropyrrolo[2,3-c]pyrrol-1-yl]-3,4-dihydro-2H- 1-benzopyran-3-yl]-3-amino-4,6-dimethylthieno[2,3-b]pyridine-2- carboxamide; 228: (6aS,7aR)-N-[(3R)-8-cyano-7-{3,8-diazabicyclo[3.2.1]octan-3-yl}-5- fluoro-3,4-dihydro-2H-1-benzopyran-3-yl]-5H,6H,6aH,7H,7aH- cyclopropa[c]1,8-naphthyridine-2-carboxamide; 229: (6aR,7aS)-N-[(3R)-8-cyano-{3,8-diazabicyclo[3.2.1]octan-3-yl}-5- fluoro-3,4-dihydro-2H-1-benzopyran-7-3-yl]-5H,6H,6aH,7H,7aH- cyclopropa[c]1,8-naphthyridine-2-carboxamide; 230: 3-amino-N-[(3R)-8-cyano-7-{3,8-diazabicyclo[3.2.1]octan-3-yl}-5-fluoro- 3,4-dihydro-2H-1-benzopyran-3-yl]4,6-dimethylthieno[2,3-b]pyridine-2- carboxamide; 231: N-[(3R)-7-[(3aR,6R,7aR)-6-amino-octahydro-1H-indol-1-yl]-3,4-dihydro- 2H-1-benzopyran-3-yl]-3-amino-6-methylthieno[2,3-b]pyridine-2- carboxamide; 232: N-[(3R)-7-[(3aR,6S,7aR)-6-amino-octahydro-1H-indol-1-yl]-3,4-dihydro- 2H-1-benzopyran-3-yl]-3-amino-6-methylthieno[2,3-b]pyridine-2- carboxamide; 233: N-[(3R)-7-[(3aS,6R,7aS)-6-amino-octahydro-1H-indol-1-yl]-3,4-dihydro- 2H-1-benzopyran-3-yl]-3-amino-6-methylthieno[2,3-b]pyridine-2- carboxamide; 234: N-[(3R)-7-[(3aS,6S,7aS)-6-amino-octahydro-1H-indol-1-yl]-3,4-dihydro- 2H-1-benzopyran-3-yl]-3-amino-6-methylthieno[2,3-b]pyridine-2- carboxamide; 235: N-[(3R)-7-[(3aS,7aR)-octahydro-1H-pyrrolo[3,2-c]pyridin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-3-amino-6-methylthieno[2,3-b]pyridine- 2-carboxamide; 236: N-[(3R)-7-[(3aR,7aS)-octahydro-1H-pyrrolo[3,2-c]pyridin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-3-amino-6-methylthieno[2,3-b]pyridine- 2-carboxamide; 237: N-[(3R)-7-[(4aR,7aR)-4,4-difluoro-octahydro-1H-pyrrolo[3,4-b]pyridin-6- yl]-3,4-dihydro-2H-1-benzopyran-3-yl]-3-amino-6-methylthieno[2,3- b]pyridine-2-carboxamide; 238: N-[(3R)-7-[(4aS,7aS)-4,4-difluoro-octahydro-1H-pyrrolo[3,4-b]pyridin-6- yl]-3,4-dihydro-2H-1-benzopyran-3-yl]-3-amino-6-methylthieno[2,3- b]pyridine-2-carboxamide; 239: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-methoxy-3-methylpyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 240: 3-amino-N-[(6S)-2-[(3R,4R)-3-amino-4-methoxy-3-methylpyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 241: 3-amino-N-[(3R)-6-cyano-7-{3,8-diazabicyclo[3.2.1]octan-3-yl}-5-fluoro- 3,4-dihydro-2H-1-benzopyran-3-yl]-4,6-dimethylthieno[2,3-b]pyridine-2- carboxamide; 242: N-[(3R)-7-[(4aR,7aR)-octahydro-1H-pyrrolo[3,4-c]pyridin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-3-amino-6-methylthieno[2,3-b]pyridine- 2-carboxamide; 243: N-[(3R)-7-[(4aS,7aS)-octahydro-1H-pyrrolo[3,4-c]pyridin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-3-amino-6-methylthieno[2,3-b]pyridine- 2-carboxamide; 244: 3-amino-N-[(3R)-7-[(2R,5R)-5-amino-2-(trifluoromethyl)piperidin-1-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 245: 3-amino-N-[(3R)-7-[(2S,5S)-5-amino-2-(trifluoromethyl)piperidin-1-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 246: 3-amino-N-[(3R)-7-[(2R,5S)-5-amino-2-(trifluoromethyl)piperidin-1-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 247: 3-amino-N-[(3R)-7-[(2S,5R)-5-amino-2-(trifluoromethyl)piperidin-1-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 248: N-[(3R)-7-[(3aS)-3a-amino-octahydrocyclopenta[c]pyrrol-2-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-3-amino-6-methylthieno[2,3-b]pyridine- 2-carboxamide; 249: N-[(3R)-7-[(3aR)-3a-amino-octahydrocyclopenta[c]pyrrol-2-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-3-amino-6-methylthieno[2,3-b]pyridine- 2-carboxamide; 250: 3-amino-N-[(3R)-7-[(3R,4R)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]- 5-fluoro-3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide; 251: 3-amino-N-[(3R)-7-[(3S,4S)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]- 5-fluoro-3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide; 252: 3-amino-N-[(2S)-6-[(3R,4R)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]- 1,2,3,4-tetrahydronaphthalen-2-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 253: 3-amino-N-[(2S)-6-[(3S,4S)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]- 1,2,3,4-tetrahydronaphthalen-2-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 254: 3-amino-N-[(6S)-2-[(3S,4R)-3-amino-4-ethoxypyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 255: 3-amino-N-[(6S)-2-[(3R,4S)-3-amino-4-ethoxypyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 256: 3-amino-N-[(3R)-7-[(4S)-4-amino-3,3-difluoropyrrolidin-1-yl]-3,4-dihydro- 2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 257: 3-amino-N-[(3R)-7-[(4R)-4-amino-3,3-difluoropyrrolidin-1-yl]-3,4-dihydro- 2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 258: 3-amino-N-[(3R)-7-[(8R)-8-amino-2-oxa-6-azaspiro[3.4]octan-6-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 259: 3-amino-N-[(3R)-7-[(8S)-8-amino-2-oxa-6-azaspiro[3.4]octan-6-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 260: 3-amino-N-[(3R)-7-[(2S,4R)-4-amino-2-(methoxymethyl)pyrrolidin-1-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 261: 3-amino-N-[(3R)-7-[(2R,4S)-4-amino-2-(methoxymethyl)pyrrolidin-1-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 262: 3-amino-N-[(3R)-7-[(2R,4R)-4-amino-2-(methoxymethyl)pyrrolidin-1-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 263: 3-amino-N-[(3R)-7-[(2S,4S)-4-amino-2-(methoxymethyl)pyrrolidin-1-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 264: (6aS,7aR)-N-[(3R)-6-cyano-7-{3,8-diazabicyclo[3.2.1]octan-3-yl}-5- fluoro-3,4-dihydro-2H-1-benzopyran-7-3-yl]-5H,6H,6aH,7H,7aH- cyclopropa[c]1,8-naphthyridine-2-carboxamide; 265: (6aR,7aS)-N-[(3R)-6-cyano-7-{3,8-diazabicyclo[3.2.1]octan-3-yl}-5- fluoro-3,4-dihydro-2H-1-benzopyran-7-3-yl]-5H,6H,6aH,7H,7aH- cyclopropa[c]1,8-naphthyridine-2-carboxamide; 266: 7-amino-N-[(6S)-2-[(3S,4S)-3-acetamido-4-methoxypyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-3-methylthieno[2,3-b]pyrazine-6-carboxamide; 267: 3-amino-N-[(2S)-6-[(3S,4R)-3-amino-4-ethoxypyrrolidin-1-yl]-1,2,3,4- tetrahydrophthalen-2-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 268: 3-amino-N-[(2S)-6-[(3R,4S)-3-amino-4-ethoxypyrrolidin-1-yl]-1,2,3,4- tetrahydrophthalen-2-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 269: 3-amino-N-[(6S)-2-[(3S,4R)-3-amino-4-methoxypyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 270: 3-amino-N-[(6S)-2-[(3R,4S)-3-amino-4-methoxypyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 271: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-(propan-2-yloxy)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinazolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 272: 3-amino-N-[(6R)-2-[(3S,4S)-3-amino-4-(propan-2-yloxy)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinazolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 273: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-5,6,7,8- tetrahydroquinazolin-6-yl]-4,6-dimethylthieno[2,3-b]pyridine-2- carboxamide; 274: 3-amino-N-[(6R)-2-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-5,6,7,8- tetrahydroquinazolin-6-yl]-4,6-dimethylthieno[2,3-b]pyridine-2- carboxamide; 275: 3-amino-N-[(3R)-7-[(3R,4R)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-4,6-dimethylthieno[2,3-b]pyridine-2- carboxamide; 276: 3-amino-N-[(3R)-7-[(3S,4S)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-4,6-dimethylthieno[2,3-b]pyridine-2- carboxamide; 277: 3-amino-N-[(3R)-7-[(3R,4R)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]- 5,8-difluoro-3,4-dihydro-2H-1-benzopyran-3-yl]-4,6-dimethylthieno[2,3- b]pyridine-2-carboxamide; 278: 3-amino-N-[(3R)-7-[(3S,4S)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]- 5,8-difluoro-3,4-dihydro-2H-1-benzopyran-3-yl]-4,6-dimethylthieno[2,3- b]pyridine-2-carboxamide; 279: 7-amino-N-[(6S)-2-[(3S,4S)-4-amino-3-methoxy-3-methylpyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-3-methylthieno[2,3-b]pyrazine-6- carboxamide; 280: 7-amino-N-[(6S)-2-[(3R,4R)-4-amino-3-methoxy-3-methylpyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-3-methylthieno[2,3-b]pyrazine-6- carboxamide; 281: 3-amino-N-[(3R)-7-[(3S,4S)-4-amino-3-methoxy-3-methylpyrrolidin-1-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 282: 3-amino-N-[(3R)-7-[(3R,4R)-4-amino-3-methoxy-3-methylpyrrolidin-1-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 283: 3-amino-N-[(3R)-7-[(2S,3R,4S)-4-amino-3-methoxy-2-methylpyrrolidin- 1-yl]-3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 284: 3-amino-N-[(3R)-7-[(2R,3S,4R)-4-amino-3-methoxy-2-methylpyrrolidin- 1-yl]-3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 285: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-cyclobutoxypyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 286: 3-amino-N-[(3R)-7-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]- 2H,3H,4H-pyrano[2,3-b]pyridin-3-yl]-4,6-dimethylthieno[2,3-b]pyridine-2- carboxamide; 287: 3-amino-N-[(3R)-7-[(3S,4S)-3-amino-4-(propan-2-yloxy)pyrrolidin-1-yl]- 2H,3H,4H-pyrano[2,3-b]pyridin-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 288: 3-amino-N-[(3R)-7-[(3R)-3-amino-pyrrolidin-1-yl]-3,4-dihydro-2H-1- benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 289: N-[(3R)-7-[(3aR,6aS)-3a-methoxy-octahydropyrrolo[2,3-c]pyrrol-5-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-3-amino-6-methylthieno[2,3- b]pyridine-2-carboxamide; 290: N-[(3R)-7-[(3aS,6aR)-3a-methoxy-octahydropyrrolo[2,3-c]pyrrol-5-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-3-amino-6-methylthieno[2,3- b]pyridine-2-carboxamide; 291: N-[(3R)-7-[(3aS,6aS)-3a-methoxy-octahydropyrrolo[2,3-c]pyrrol-2-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-3-amino-6-methylthieno[2,3- b]pyridine-2-carboxamide; 292: N-[(3R)-7-[(3aR,6aR)-3a-methoxy-octahydropyrrolo[2,3-c]pyrrol-2-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-3-amino-6-methylthieno[2,3- b]pyridine-2-carboxamide; 293: 3-amino-N-[(6S)-2-[(3S,4S)-3-acetamido-3-methoxypyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinazolin-6-yl]4,6-dimethylthieno[2,3-b]pyridine-2- carboxamide; 294: 3-amino-N-[(3R)-7-[(3R,4S)-3-amino-4-(difluoromethyl)pyrrolidin-1-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 295: 3-amino-N-[(3R)-7-[(3S,4R)-3-amino-4-(difluoromethyl)pyrrolidin-1-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 296: 3-amino-N-[(6S)-2-[(3R,4R)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-4,6-dimethylthieno[2,3-b]pyridine-2- carboxamide; 297: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-4,6-dimethylthieno[2,3-b]pyridine-2- carboxamide; 298: 7-amino-N-[(6S)-2-[(3R,4R)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-3-methylthieno[2,3-b]pyrazine-6- carboxamide; 299: 7-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-3-methylthieno[2,3-b]pyrazine-6- carboxamide; 300: 3-amino-N-[(6S)-2-[(3R,4R)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]- 3-fluoro-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 301: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]- 3-fluoro-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 302: 3-amino-N-[(6R)-2-[(3R,4R)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]- 3-fluoro-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 303: 3-amino-N-[(6R)-2-[(3S,4S)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]- 3-fluoro-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 304: N-[(3R)-7-[(3aS,6aS)-octahydropyrrolo[3,4-b]pyrrol-5-yl]-3,4-dihydro-2H- 1-benzopyran-3-yl]-3-amino-6-methylthieno[2,3-b]pyridine-2- carboxamide; 305: N-[(3R)-7-[(3aR,6aR)-octahydropyrrolo[3,4-b]pyrrol-5-yl]-3,4-dihydro- 2H-1-benzopyran-3-yl]-3-amino-6-methylthieno[2,3-b]pyridine-2- carboxamide; 306: 3-amino-N-[(3R)-7-{2,6-diazaspiro[3.4]octan-6-yl}-3,4-dihydro-2H-1- benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 307: 3-amino-N-[(3R)-7-[(5S,9S)-9-amino-1-oxa-7-azaspiro[4.4]nonan-7-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 308: 3-amino-N-[(3R)-7-[(5R,9R)-9-amino-1-oxa-7-azaspiro[4.4]nonan-7-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 309: 3-amino-N-[(3R)-7-[(5S,9R)-9-amino-1-oxa-7-azaspiro[4.4]nonan-7-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 310: 3-amino-N-[(3R)-7-[(5R,9S)-9-amino-1-oxa-7-azaspiro[4.4]nonan-7-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 311: 3-amino-N-[(6S)-2-[(3S,4S)-3-methoxy-4-(methylamino)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 312: 3-amino-N-[(6S)-2-[(3S,4S)-3-methoxy-4-(methylamino)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-4,6-dimethylthieno[2,3-b]pyridine-2- carboxamide; 313: 3-amino-N-[(3R)-7-[(3R,4R)-3-amino-4-(ethoxymethyl)pyrrolidin-1-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 314: 3-amino-N-[(3R)-7-[(3S,4S)-3-amino-4-(ethoxymethyl)pyrrolidin-1-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 315: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-methoxypiperidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 316: 3-amino-N-[(6S)-2-[(3R,4R)-3-amino-4-methoxypiperidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 317: 3-amino-N-[(3R)-7-[(3S,4S)-3-amino-4-methoxypiperidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-4,6-dimethylthieno[2,3-b]pyridine-2- carboxamide; 318: 3-amino-N-[(3R)-7-[(3R,4R)-3-amino-4-methoxypiperidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-4,6-dimethylthieno[2,3-b]pyridine-2- carboxamide; 319: 7-amino-N-[(2S)-6-[(3S,4S)-3-amino-4-(propan-2-yloxy)pyrrolidin-1-yl]- 1,2,3,4-tetrahydrophthalen-2-yl]-3-methylthieno[2,3-b]pyrazine-6- carboxamide; 320: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-(propan-2-yloxy)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 321: 3-amino-N-[(6S)-2-[(3S,4R)-3-amino-4-(propan-2-yloxy)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 322: 3-amino-N-[(6S)-2-[(3R,4S)-3-amino-4-(propan-2-yloxy)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 323: 3-amino-N-[(3R)-7-[(3S,4R)-3-amino-4-ethoxypyrrolidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-4,6-dimethylthieno[2,3-b]pyridine-2- carboxamide; 324: 3-amino-N-[(3R)-7-[(3R,4S)-3-amino-4-ethoxypyrrolidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-4,6-dimethylthieno[2,3-b]pyridine-2- carboxamide; 325: 3-amino-N-[(3R)-7-[(3S,4S)-4-amino-3-methoxy-3-methylpyrrolidin-1-yl]- 2H,3H,4H-pyrano[2,3-b]pyridin-3-yl)-6-methylthieno[2,3-b]pyridine-2- carboxamide; 326: 3-amino-N-[(3R)-7-[(3R,4R)-4-amino-3-methoxy-3-methylpyrrolidin-1-yl]- 2H,3H,4H-pyrano[2,3-b]pyridin-3-yl)-6-methylthieno[2,3-b]pyridine-2- carboxamide; 327: 3-amino-N-[(6S)-2-[(3R,4S)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 328: 3-amino-N-[(6S)-2-[(3S,4R)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 329: N-[(6S)-2-[(4aS,7aS)-4,4-difluoro-octahydro-1H-pyrrolo[3,4-b]pyridin-6- yl]-5,6,7,8-tetrahydroquinolin-6-yl]-3-amino-6-methylthieno[2,3- b]pyridine-2-carboxamide; 330: N-[(6S)-2-[(4aR,7aR)-4,4-difluoro-octahydro-1H-pyrrolo[3,4-b]pyridin-6- yl]-5,6,7,8-tetrahydroquinolin-6-yl]-3-amino-6-methylthieno[2,3- b]pyridine-2-carboxamide; 331: 3-amino-N-[(6S)-2-[(3R,4R)-3-hydroxy-3-methyl-4- (methylamino)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide; 332: 3-amino-N-[(6S)-2-[(3S,4R)-3-hydroxy-3-methyl-4- (methylamino)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide; 333: 3-amino-N-[(3R)-7-[(2S,3S,4S)-3-amino-4-methoxy-2-methylpyrrolidin- 1-yl]-3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 334: 3-amino-N-[(3R)-7-[(2S,3S,4R)-4-amino-3-methoxy-2-methylpyrrolidin- 1-yl]-3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 335: 3-amino-N-[(3R)-7-[(2R,3R,4R)-3-amino-4-methoxy-2-methylpyrrolidin- 1-yl]-3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 336: 3-amino-N-[(3R)-7-[(2R,3R,4S)-4-amino-3-methoxy-2-methylpyrrolidin- 1-yl]-3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 337: 3-amino-N-[(3R)-7-[(8R)-8-amino-5-oxa-2-azaspiro[3.4]octan-2-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 338: 3-amino-N-[(3R)-7-[(8R)-8-amino-5-oxa-2-azaspiro[3.4]octan-2-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 339: 3-amino-N-[(3R)-7-[(4R,8R)-8-amino-1-oxa-6-azaspiro[3.4]octan-6-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 340: 3-amino-N-[(3R)-7-[(4S,8S)-8-amino-1-oxa-6-azaspiro[3.4]octan-6-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 341: 3-amino-N-[(6S)-2-[(3S,4R)-4-amino-3-(methoxymethyl)-3- methylpyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide; 342: 3-amino-N-[(6S)-2-[(3R,4R)-4-amino-3-(methoxymethyl)-3- methylpyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide; 343: 3-amino-N-[(6S)-2-[(3S,4S)-4-amino-3-(methoxymethyl)-3- methylpyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide; 344: 3-amino-N-[(6S)-2-[(3R,4S)-4-amino-3-(methoxymethyl)-3- methylpyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide; 345: 3-amino-N-[(6S)-2-[(3R,4R)-3-amino-4-(difluoromethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 346: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-(difluoromethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 347: 3-amino-N-[(6S)-2-[(3R,4S)-3-amino-4-(difluoromethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 348: 3-amino-N-[(3R)-7-[(3R,4R)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]- 2H,3H,4H-pyrano[2,3-b]pyridin-3-yl)-4,6-dimethylthieno[2,3-b]pyridine-2- carboxamide; 349: 3-amino-N-[(3R)-7-[(3S,4S)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]- 2H,3H,4H-pyrano[2,3-b]pyridin-3-yl)-4,6-dimethylthieno[2,3-b]pyridine-2- carboxamide; 350: 3-amino-N-[(3R)-7-[(3S,4S)-3-hydroxy-4-(methylamino)pyrrolidin-1-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 351: 3-amino-N-[(3R)-7-[(7R)-7-amino-2-oxa-5-azaspiro[3.4]octan-5-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 352: 3-amino-N-[(3R)-7-[(7S)-7-amino-2-oxa-5-azaspiro[3.4]octan-5-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 353: N-[(6S)-2-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]5,6,7,8- tetrahydroquinolin-6-yl]-1-ethyl-1H-pyrrolo[2,3-b]pyridine-5- carboxamide; 354: 3-amino-N-[(6S)-2-{3,8-diazabicyclo[3.2.1]octan-3-yl}-5,6,7,8- tetrahydroquinolin-6-yl]-4,6-dimethylthieno[2,3-b]pyridine-2- carboxamide; 355: 5-chloro-N-[(3R)-7-{3,8-diazabicyclo[3.2.1]octan-3-yl}-5,8-difluoro-3,4- dihydro-2H-1-benzopyran-3-yl]-7-ethyl-7H-pyrrolo[2,3-c]pyridine-3- carboxamide; 356: 5-chloro-N-[(3R)-8-cyano-7-{3,8-diazabicyclo[3.2.1]octan-3-yl}-5-fluoro- 3,4-dihydro-2H-1-benzopyran-3-yl]-7-ethyl-7H-pyrrolo[2,3-c]pyridazine- 3-carboxamide; 357: 3-amino-N-[(6S)-2-[(3S,4R)-3-amino-4-(1,1-difluoroethoxy)pyrrolidin-1- yl]5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 358: 3-amino-N-[(6S)-2-[(3R,4S)-3-amino-4-(1,1-difluoroethoxy)pyrrolidin-1- yl]5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 359: (6aS,7aR)-N-[(2S)-6-{3,8-diazabicyclo[3.2.1]octan-3-yl}-5- (difluoromethyl)-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl]- 5H,6H,6aH,7H,7aH-cyclopropa[c]1,8-naphthyridine-2-carboxamide; 360: (6aR,7aS)-N-[(2S)-6-{3,8-diazabicyclo[3.2.1]octan-3-yl}-5- (difluoromethyl)-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl]- 5H,6H,6aH,7H,7aH-cyclopropa[c]1,8-naphthyridine-2-carboxamide; 361: (6aS,7aR)-N-[(2R)-6-{3,8-diazabicyclo[3.2.1]octan-3-yl}-5- (difluoromethyl)-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl]- 5H,6H,6aH,7H,7aH-cyclopropa[c]1,8-naphthyridine-2-carboxamide; 362: (6aR,7aS)-N-[(2R)-6-{3,8-diazabicyclo[3.2.1]octan-3-yl}-5- (difluoromethyl)-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl]- 5H,6H,6aH,7H,7aH-cyclopropa[c]1,8-naphthyridine-2-carboxamide; 363: 3-amino-N-[(6S)-2-[(3R,4S)-3-amino-4-(trifluoromethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 364: 3-amino-N-[(6S)-2-[(3S,4R)-3-amino-4-(trifluoromethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 365: 7-amino-N-[(6S)-2-[(8R)-8-amino-2-oxa-6-azaspiro[3.4]octan-6-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-3-methylthieno[2,3-b]pyrazine-6- carboxamide; 366: 7-amino-N-[(6S)-2-[(8S)-8-amino-2-oxa-6-azaspiro[3.4]octan-6-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-3-methylthieno[2,3-b]pyrazine-6- carboxamide; 367: 3-amino-N-[(6S)-2-[(1R,5S)-9,9-difluoro-2,7-diazabicyclo[3.3.1]nonan-7- yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 368: 3-amino-N-[(6S)-2-[(1S,5R)-9,9-difluoro-2,7-diazabicyclo[3.3.1]nonan-7- yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 369: 3-amino-N-[(3R)-7-[(3S)-3-aminopyrrolidin-1-yl]-3,4-dihydro-2H-1- benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 370: N-[(6S)-2-[(3R,4S)-3-amino-4-(difluoromethyl)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-1-ethyl-1H-pyrrolo[2,3-b]pyridine-5- carboxamide; 371: N-[(6S)-2-[(3S,4R)-3-amino-4-(difluoromethyl)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-1-ethyl-1H-pyrrolo[2,3-b]pyridine-5- carboxamide; 372: 3-amino-N-[(6S)-2-[(3R,4S)-3-(difluoromethyl)-4-acetamidopyrrolidin-1- yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 373: 3-amino-N-[(3R)-7-[3-amino-3-(methoxymethyl)azetidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 374: 3-amino-N-[(6S)-2-[(3S)-3-(difluoromethylpiperazin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 375: 3-amino-N-[(6S)-2-[(3R)-3-(difluoromethylpiperazin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 376: 3-amino-N-[(6S)-2-[(3S,4R)-3-(difluoromethyl)-4- (methylamino)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide; 377: 3-amino-N-[(6S)-2-[(3R,4S)-3-(difluoromethyl)-4- (methylamino)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide; 378: 3-amino-N-[(3R)-7-[(3R,4S)-3-amino-4-(difluoromethyl)pyrrolidin-1-yl]- 2H,3H,4H-pyrano[2,3-b]pyridin-3-yl)-6-methylthieno[2,3-b]pyridine-2- carboxamide; 379: 3-amino-N-[(3R)-7-[(3S,4R)-3-amino-4-(difluoromethyl)pyrrolidin-1-yl]- 2H,3H,4H-pyrano[2,3-b]pyridin-3-yl)-6-methylthieno[2,3-b]pyridine-2- carboxamide; 380: 3-amino-N-[(6S)-2-[(3R,4S)-3-amino-4-(difluoromethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinozolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 381: 3-amino-N-[(6S)-2-[(3S,4R)-3-amino-4-(difluoromethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinozolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 382: 3-amino-N-[(6R)-2-[(3S,4R)-3-amino-4-(difluoromethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinozolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 383: 3-amino-N-[(6R)-2-[(3R,4S)-3-amino-4-(difluoromethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinozolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 384: 3-amino-N-[(6S)-2-[(3R,4S)-3-amino-4-(difluoromethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 385: 3-amino-N-[(6S)-2-[(3S,4R)-3-amino-4-(difluoromethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 386: 3-amino-N-[(6S)-2-[(3R)-3-amino-3-(hydroxymethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 387: 3-amino-N-[(6S)-2-[(3S)-3-amino-3-(hydroxymethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 388: 3-amino-N-[(6S)-2-[(3R)-3-amino-3-(hydroxymethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 389: 3-amino-N-[(6S)-2-[(3S)-3-amino-3-(hydroxymethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 390: 3-amino-N-[(6S)-2-[(5S,9S)-9-amino-1-oxa-7-azaspiro[4.4]nonan-7-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 391: 3-amino-N-[(6S)-2-[(5S,9S)-9-amino-1-oxa-7-azaspiro[4.4]nonan-7-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 392: 3-amino-N-[(6S)-2-[(5R,9R)-9-amino-1-oxa-7-azaspiro[4.4]nonan-7-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 393: 3-amino-N-[(6S)-2-[(5R,9R)-9-amino-1-oxa-7-azaspiro[4.4]nonan-7-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 394: N-[(6S)-2-[(3aR,6aS)-3a-amino-hexahydro-1H-furo[3,4-c]pyrrol-5-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-3-amino-6-methylthieno[2,3-b]pyridine- 2-carboxamide; 395: N-[(6S)-2-[(3aS,6aR)-3a-amino-hexahydro-1H-furo[3,4-c]pyrrol-5-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-3-amino-6-methylthieno[2,3-b]pyridine- 2-carboxamide; 396: 3-amino-6-methyl-N-[(6S)-2-[(1R,5S,9r)-9-amino-3-oxa-7- azabicyclo[3.3.1]nonan-9-yl]-5,6,7,8-tetrahydroquinolin-6-yl]thieno[2,3- b]pyridine-2-carboxamide; 397: 3-amino-6-methyl-N-[(6S)-2-[(1R,5S,9s)-9-amino-3-oxa-7- azabicyclo[3.3.1]nonan-9-yl]-5,6,7,8-tetrahydroquinolin-6-yl]thieno[2,3- b]pyridine-2-carboxamide; 398: 3-amino-N-[(6S)-2-[(7R)-7-amino-5-oxa-2-azaspiro[3.4]octan-2-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 399: 3-amino-N-[(6S)-2-[(7S)-7-amino-5-oxa-2-azaspiro[3.4]octan-2-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 400: N-[(6S)-2-[(3R,4R)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-1-ethyl-1H-pyrrolo[2,3-b]pyridine-5- carboxamide; 401: N-[(6S)-2-[(3S,4S)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-1-ethyl-1H-pyrrolo[2,3-b]pyridine-5- carboxamide; 402: 1-ethyl-N-[(6S)-2-[(3S,4S)-3-methoxy-4-(methylamino)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-1H-pyrrolo[2,3-b]pyridine-5- carboxamide; 403: N-[(6S)-2-[(8R)-8-amino-2-oxa-6-azaspiro[3.4]octan-6-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-1-ethyl-1H-pyrrolo[2,3-b]pyridine-5- carboxamide; 404: N-[(6S)-2-[(8S)-8-amino-2-oxa-6-azaspiro[3.4]octan-6-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-1-ethyl-1H-pyrrolo[2,3-b]pyridine-5- carboxamide; 405: 3-amino-N-[(6S)-2-[(4R,5S)-4-amino-1-oxa-7-azaspiro[4.4]nonan-7-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 406: 3-amino-N-[(6S)-2-[(4S,5R)-4-amino-1-oxa-7-azaspiro[4.4]nonan-7-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 407: 3-amino-N-[(6S)-2-[(4S,5S)-4-amino-1-oxa-7-azaspiro[4.4]nonan-7-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 408: 3-amino-N-[(6S)-2-[(4R,5R)-4-amino-1-oxa-7-azaspiro[4.4]nonan-7-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 409: 3-amino-N-[(3R)-7-[(4R,5R)-4-amino-1-oxa-7-azaspiro[4.4]nonan-7-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 410: 3-amino-N-[(3R)-7-[(4R,5R)-4-amino-1-oxa-7-azaspiro[4.4]nonan-7-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 411: 3-amino-N-[(3R)-7-[(4S,5S)-4-amino-1-oxa-7-azaspiro[4.4]nonan-7-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 412: 3-amino-N-[(3R)-7-[(4S,5R)-4-amino-1-oxa-7-azaspiro[4.4]nonan-7-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 413: 3-amino-N-[(3R)-5-fluoro-7-[(1R)-1-methyl-9-oxa-3,7- diazabicyclo[3.3.1]nonan-3-yl]-3,4-dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide; 414: 3-amino-N-[(3R)-5-fluoro-7-[(1S)-1-methyl-9-oxa-3,7- diazabicyclo[3.3.1]nonan-3-yl]-3,4-dihydro-2H-1-benzopyran-3-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide; 415: 3-amino-N-[(3R)-7-[(3R,4R)-3-amino-4-methoxypyrrolidin-1-yl]-5,6- difluoro-3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide; 416: 3-amino-N-[(3R)-7-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-5,6- difluoro-3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3- b]pyridine-2-carboxamide; 417: 3-amino-N-[(2S)-7,8-difluoro-6-(piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 418: 3-amino-N-[(2R)-7,8-difluoro-6-(piperazin-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 419: 3-amino-N-[(6S)-2-[(2R,3R)-3-amino-2-(methoxymethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 420: 3-amino-N-[(6S)-2-[(2S,3S)-3-amino-2-(methoxymethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 421: N-[(6S)-2-[(3R,4S)-3-amino-4-(trifluoromethyl)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-1-ethyl-1H-pyrrolo[2,3-b]pyridine-5- carboxamide; 422: N-[(6S)-2-[(3S,4R)-3-amino-4-(trifluoromethyl)pyrrolidin-1-yl]-5,6,7,8- tetrahydroquinolin-6-yl]-1-ethyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide; 423: 3-amino-N-[(3R)-7-[(3R,4R)-3-amino-4-(fluoromethyl)pyrrolidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 424: 3-amino-N-[(3R)-7-[(3S,4S)-3-amino-4-(fluoromethyl)pyrrolidin-1-yl]-3,4- dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 425: N-[(3R)-7-[(3aS,6R,6aS)-6-amino-hexahydro-2H-furo[3,2-b]pyrrol-4-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-3-amino-6-methylthieno[2,3- b]pyridine-2-carboxamide; 426: N-[(3R)-7-[(3aR,6R,6aR)-6-amino-hexahydro-2H-furo[3,2-b]pyrrol-4-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-3-amino-6-methylthieno[2,3- b]pyridine-2-carboxamide; 427: 3-amino-N-[(6S)-2-[(3R,4S)-4-amino-3-methoxy-3-methylpyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 428: 3-amino-N-[(6S)-2-[(3S,4R)-4-amino-3-methoxy-3-methylpyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 429: 3-amino-N-[(6S)-2-{7-amino-3,3-dioxo-3λ^(⊖)thia-9- azabicyclo[3.3.1]nonan-9-yl}-5,6,7,8-tetrahydroquinolin-6-yl]-6- methylthieno[2,3-b]pyridine-2-carboxamide; 430: 3-amino-N-[(6S)-2-[(5S,9R)-9-amino-2-oxa-7-azabicyclo[4.4]nonan-7-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 431: 3-amino-N-[(6S)-2-[(5R,9S)-9-amino-2-oxa-7-azabicyclo[4.4]nonan-7-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 432: 3-amino-N-[(6S)-2-[(5R,9S)-9-amino-2-oxa-7-azabicyclo[4.4]nonan-7-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 433: 3-amino-N-[(3R)-7-[(5S,9S)-9-amino-2-oxa-7-azabicyclo[4.4]nonan-7-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 434: N-[(6S)-2-[(3aR,6aS)-3a-methoxy-octahydropyrrolo[2,3-c]pyrrol-5-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-3-amino-6-methylthieno[2,3-b]pyridine- 2-carboxamide; 435: N-[(6S)-2-[(3aS,6aR)-3a-methoxy-octahydropyrrolo[2,3-c]pyrrol-5-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-3-amino-6-methylthieno[2,3-b]pyridine- 2-carboxamide; 436: 3-amino-N-[(2S)-6-[(3R,4R)-3-amino-4-(fluoromethyl)pyrrolidin-1-yl]- 1,2,3,4-tetrahydronaphthalen-2-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 437: 3-amino-N-[(6S)-2-[(5R,9R)-9-amino-2-oxa-7-azaspiro[4.4]nonan-7-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 438: 3-amino-N-[(6S)-2-[(5S,9S)-9-amino-2-oxa-7-azaspiro[4.4]nonan-7-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 439: 3-amino-N-[(3R)-7-[(5R,9R)-9-amino-2-oxa-7-azaspiro[4.4]nonan-7-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 440: 3-amino-N-[(3R)-7-[(5S,9R)-9-amino-2-oxa-7-azaspiro[4.4]nonan-7-yl]- 3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 441: 3-amino-N-[(6S)-2-[(3R,4R)-3-(fluoromethyl)-4-(methylamino)pyrrolidin- 1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 442: 3-amino-N-[(6S)-2-[(3S,4S)-3-(fluoromethyl)-4-(methylamino)pyrrolidin- 1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 443: 3-amino-N-[(3R)-7-[(3R,4R)-3-(fluoromethyl)-4-(methylamino)pyrrolidin- 1-yl]-3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 444: 3-amino-N-[(3R)-7-[(3S,4S)-3-(fluoromethyl)-4-(methylamino)pyrrolidin- 1-yl]-3,4-dihydro-2H-1-benzopyran-3-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 445: 3-amino-N-[(6R)-2-[(3R,4R)-3-amino-4-(fluoromethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 446: 3-amino-N-[(6R)-2-[(3S,4S)-3-amino-4-(fluoromethyl)pyrrolidin-1-yl]- 5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 447: 3-amino-N-[(6R)-2-[(3S,4S)-3-amino-4-(fluoromethyl)pyrrolidin-1-yl]- 1,2,3,4-tetrahydronaphthalen-2-yl]-6-methylthieno[2,3-b]pyridine-2- carboxamide; 448: N-((2S)-6-(9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl)-1,2,3,4- tetrahydronaphthalen-2-yl]-7-amino-3-methylthieno[2,3-b]pyrazine-6- carboxamide; 449: N-((2S)-6-(9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl)-1,2,3,4- tetrahydronaphthalen-2-yl]-3-amino-6-methylthieno[2,3-b]pyridine-2- carboxamide; 450: N-((2R)-6-(9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl)-1,2,3,4- tetrahydronaphthalen-2-yl]-7-amino-3-methylthieno[2,3-b]pyrazine-6- carboxamide; 451: N-((2R)-6-(9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl)-1,2,3,4- tetrahydronaphthalen-2-yl]-3-amino-6-methylthieno[2,3-b]pyridine-2- carboxamide; 452: (R)-N-(6-(1,4-diazepan-1-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]-7- amino-3-methylthieno[2,3-b]pyrazine-6-carboxamide; 453: 7-amino-N-((R)-6-((S)-6-fluoro-1,4-diazepan-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl]-3-methylthieno[2,3-b]pyrazine-6- carboxamide; 454: (S)-7-amino-N-(6-(6,6-difluoro-1,4-diazepan-1-yl)-1,2,3,4- tetrahydronaphthalen-2-yl]-3-methylthieno[2,3-b]pyrazine-6- carboxamide; 455: (S)-N-(6-(1,4-diazepan-1-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]-7- amino-3-methylthieno[2,3-b]pyrazine-6-carboxamide; 456: N-((2S)-6-(3-oxa-7,9-diazabicyclo[3.3.1]nonan-3-yl)-1,2,3,4- tetrahydronaphthalen-2-yl]-7-amino-3-methylthieno[2,3-b]pyrazine-6- carboxamide; 457: (R)-7-bromo-N-(7-(piperazin-1-yl)chroman-3-yl)-pyrazolo[1,5-a]pyridine- 3-carboxamide; 458: (R)-7-methyl-N-(7-(piperazin-1-yl)chroman-3-yl)-pyrazolo[1,5-a]pyridine- 3-carboxamide; 459: (R)-1-acetyl-N-(7-(piperazin-1-yl)chroman-3-yl)-1,2,3,4- tetrahydronaphthalen-6-carboxamide; 460: (R)-N-(7-(piperazin-1-yl)chroman-3-yl)pyrazolo[1,5-a]pyridine-3- carboxamide; 461: (R)-5-methoxy-N-(7-(piperazin-1-yl)chroman-3-yl)pyrazolo[1,5- a]pyridine-3-carboxamide; 462: (R)-6-chloro-N-(7-(piperazin-1-yl)chroman-3-yl)pyrazolo[1,5-a]pyridine- 3-carboxamide; 463: (R)-5,7-dimethyl-N-(7-(piperazin-1-yl)chroman-3-yl)pyrazolo[1,5-a]pyridine- 3-carboxamide; 464: (R)-6-chloro-N-(7-(piperazin-1-yl)chroman-3-yl)imidazo[1,2-b]pyridazine- 2-carboxamide; 465: (R)-5-methyl-N-(7-(piperazin-1-yl)chroman-3-yl)pyrazolo[1,5-a]pyridine- 3-carboxamide; 466: (R)-N-(7-(piperazin-1-yl)chroman-3-yl)pyrazolo[1,5-a]pyridine-3- carboxamide; 467: (R)-6-((3-chlorobemzyl)amino)-N-(7-(piperazin-1-yl)chroman-3- yl)nicotinamide; 468: (R)-N-(7-(piperazin-1-yl)chroman-3-yl)-6-((pyridine-3- ylmethyl)amino)nicotinamide; 469: (R)-N-(7-(piperazin-1-yl)chroman-3-yl)-6-((3-trifluoromethyl)benzyl) amino)nicotinamide; 470: (R)-N-(7-(piperazin-1-yl)chroman-3-yl)-6-((pyridine-3- ylmethyl)amino)nicotinamide; 471: (R)-6-(((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)amino)-N-(7- (piperazin-1-yl)chroman-3-yl)-nicotinamide; 472: (R)-6-(((2,3-dihydrobenzofuran-5-yl)methyl)amino)-N-(7-(piperazin-1- yl)chroman-3-yl)-nicotinamide; 473: (R)-6-((3-acetamidobenzyl)amino)-N-(7-(piperazin-1-yl)chroman-3- yl)-nicotinamide; 474: 7-ethyl-N-[(3R)-7-(piperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3- yl]pyrazolo[1,5-a]pyridine-3-carboxamide; 475: 7-(hydroxymethyl)-N-[(3R)-7-(piperazin-1-yl)-3,4-dihydro-2H-1- benzopyran-3-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;

or a pharmaceutically acceptable salt thereof.
 15. The compound of claim 1, chosen from the following compounds: 10-1: (R)-3-amino-N-(5-fluoro-7-(piperazin-1-yl)chroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide; 10-5: (S)-3-amino-N-(5-fluoro-7-(piperazin-1-yl)chroman-3-yl)-6-methylthieno[2,3-b]pyridine-2-carboxamide; 10-15: 3-amino-N-[(3R)-5-fluoro-7-(piperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-N,6-dimethylthieno[2,3-b]pyridine-2-carboxamide; 10-16: 3-amino-N-[(3S)-5-fluoro-7-(piperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-N,6-dimethylthieno[2,3-b]pyridine-2-carboxamide; 11-1: N-((2S)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide; 11-2: N-((2R)-6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)-3-amino-6-methylthieno[2,3-b]pyridine-2-carboxamide; 23-1: 7-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-3-methylthieno[2,3-b]pyrazine-6-carboxamide; 23-2: 7-amino-N-[(6R)-2-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-3-methylthieno[2,3-b]pyrazine-6-carboxamide; 23-3: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide; 23-4: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 23-5: 3-amino-N-[(6R)-2-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 23-6: 7-amino-3-methyl-N-[(6S)-2-(piperazin-1-yl)-5,6,7,8-tetrahydroquinolin-6-yl]thieno[2,3-b]pyrazine-6-carboxamide; 23-7: 3-amino-6-methyl-N-[(6S)-2-(piperazin-1-yl)-5,6,7,8-tetrahydroquinolin-6-yl]thieno[2,3-b]pyridine-2-carboxamide; 23-8: 3-amino-6-methyl-N-[(6R)-2-(piperazin-1-yl)-5,6,7,8-tetrahydroquinolin-6-yl]thieno[2,3-b]pyridine-2-carboxamide; 23-9: 6-amino-2-methyl-N-[(6S)-2-(piperazin-1-yl)-5,6,7,8-tetrahydroquinolin-6-yl]thieno[2,3-d][1,3]thiazole-5-carboxamide; 23-12: 3-amino-N-[(6S)-2-{3,8-diazabicyclo[3.2.1]octan-3-yl}-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 23-13: 7-amino-N-[(6S)-2-{3,8-diazabicyclo[3.2.1]octan-3-yl}-5,6,7,8-tetrahydroquinolin-6-yl]-3-methylthieno[2,3-b]pyrazine-6-carboxamide; 23-14: 3-amino-4,6-dimethyl-N-[(6S)-2-(piperazin-1-yl)-5,6,7,8-tetrahydroquinolin-6-yl]thieno[2,3-b]pyridine-2-carboxamide; 23-17: 3-amino-N-[(6S)-4-fluoro-2-(piperazin-1-yl)-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 23-18: 3-amino-N-[(6S)-2-{3,8-diazabicyclo[3.2.1]octan-3-yl}-4-fluoro-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 24-1: 3-amino-N-[(6S)-2-[(3R,4R)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 24-2: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 25: 3-amino-N-[(6S)-2-[(3S,4R)-3-amino-4-(difluoromethyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 26-1: 3-amino-N-[(6S)-2-[(3S,4R)-3-(methoxymethyl)-4-(methylamino)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 26-2: 3-amino-N-[(6S)-2-[(3R,4S)-3-(methoxymethyl)-4-(methylamino)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 27-1: 3-amino-N-[(6S)-2-[(3R,4R)-3-amino-4-(fluoromethyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 27-2: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-(fluoromethyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 28-1: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-(2-methoxyethoxy)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 28-2: 3-amino-N-[(6S)-2-[(3R,4R)-3-amino-4-(2-methoxyethoxy)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 29-1: 3-amino-N-[(6S)-2-[(9S)-9-amino-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 29-2: 3-amino-N-[(6S)-2-[(9R)-9-amino-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 30-1: 3-amino-N-[(6S)-3-fluoro-2-(piperazin-1-yl)-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 30-2: 3-amino-N-[(6R)-3-fluoro-2-(piperazin-1-yl)-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 31-3: 3-amino-6-methyl-N-[(6′S)-2′-(piperazin-1-yl)-6′,7′-dihydro-5′H-spiro[cyclopropane-1,8′-quinoline]-6′-yl]thieno[2,3-b]pyridine-2-carboxamide; 31-4: 3-amino-6-methyl-N-[(6′R)-2′-(piperazin-1-yl)-6′,7′-dihydro-5′H-spiro[cyclopropane-1,8′-quinoline]-6′-yl]thieno[2,3-b]pyridine-2-carboxamide; 142: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-ethoxypyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 203: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-methoxypyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-5-fluoro-6-methylthieno[2,3-b]pyridine-2-carboxamide; 204: 3-amino-5-fluoro-6-methyl-N-[(6S)-2-(piperazin-1-yl)-5,6,7,8-tetrahydroquinolin-6-yl]thieno[2,3-b]pyridine-2-carboxamide; 205: 3-amino-6-methyl-N-[(6S,8S)-8-methyl-2-(piperazin-1-yl)-5,6,7,8-tetrahydroquinolin-6-yl]thieno[2,3-b]pyridine-2-carboxamide; 206: 3-amino-6-methyl-N-[(6R,8S)-8-methyl-2-(piperazin-1-yl)-5,6,7,8-tetrahydroquinolin-6-yl]thieno[2,3-b]pyridine-2-carboxamide; 207: 3-amino-6-methyl-N-[(6S,8R)-8-methyl-2-(piperazin-1-yl)-5,6,7,8-tetrahydroquinolin-6-yl]thieno[2,3-b]pyridine-2-carboxamide; 208: 3-amino-6-methyl-N-[(6R,8R)-8-methyl-2-(piperazin-1-yl)-5,6,7,8-tetrahydroquinolin-6-yl]thieno[2,3-b]pyridine-2-carboxamide; 210: 3-amino-N-[(6S)-2-[(3S,4S)-4-amino-3-methoxy-3-methylpyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 211: 3-amino-N-[(6S)-2-[(3R,4R)-4-amino-3-methoxy-3-methylpyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 239: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-methoxy-3-methylpyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 240: 3-amino-N-[(6S)-2-[(3R,4R)-3-amino-4-methoxy-3-methylpyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 254: 3-amino-N-[(6S)-2-[(3S,4R)-3-amino-4-ethoxypyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 255: 3-amino-N-[(6S)-2-[(3R,4S)-3-amino-4-ethoxypyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 269: 3-amino-N-[(6S)-2-[(3S,4R)-3-amino-4-methoxypyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 270: 3-amino-N-[(6S)-2-[(3R,4S)-3-amino-4-methoxypyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 279: 7-amino-N-[(6S)-2-[(3S,4S)-4-amino-3-methoxy-3-methylpyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-3-methylthieno[2,3-b]pyrazine-6-carboxamide; 280: 7-amino-N-[(6S)-2-[(3R,4R)-4-amino-3-methoxy-3-methylpyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-3-methylthieno[2,3-b]pyrazine-6-carboxamide; 285: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-cyclobutoxypyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 296: 3-amino-N-[(6S)-2-[(3R,4R)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide; 297: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide; 298: 7-amino-N-[(6S)-2-[(3R,4R)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-3-methylthieno[2,3-b]pyrazine-6-carboxamide; 299: 7-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-3-methylthieno[2,3-b]pyrazine-6-carboxamide; 300: 3-amino-N-[(6S)-2-[(3R,4R)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]-3-fluoro-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 301: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]-3-fluoro-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 302: 3-amino-N-[(6R)-2-[(3R,4R)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]-3-fluoro-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 303: 3-amino-N-[(6R)-2-[(3S,4S)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]-3-fluoro-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 311: 3-amino-N-[(6S)-2-[(3S,4S)-3-methoxy-4-(methylamino)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 312: 3-amino-N-[(6S)-2-[(3S,4S)-3-methoxy-4-(methylamino)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide; 320: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-(propan-2-yloxy)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 321: 3-amino-N-[(6S)-2-[(3S,4R)-3-amino-4-(propan-2-yloxy)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 322: 3-amino-N-[(6S)-2-[(3R,4S)-3-amino-4-(propan-2-yloxy)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 327: 3-amino-N-[(6S)-2-[(3R,4S)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 328: 3-amino-N-[(6S)-2-[(3S,4R)-3-amino-4-(methoxymethyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 331: 3-amino-N-[(6S)-2-[(3R,4S)-3-hydroxy-3-methyl-4-(methylamino)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 332: 3-amino-N-[(6S)-2-[(3S,4R)-3-hydroxy-3-methyl-4-(methylamino)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 341: 3-amino-N-[(6S)-2-[(3S,4R)-4-amino-3-(methoxymethyl)-3-methylpyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 342: 3-amino-N-[(6S)-2-[(3R,4R)-4-amino-3-(methoxymethyl)-3-methylpyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 343: 3-amino-N-[(6S)-2-[(3S,4S)-4-amino-3-(methoxymethyl)-3-methylpyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 344: 3-amino-N-[(6S)-2-[(3R,4S)-4-amino-3-(methoxymethyl)-3-methylpyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 345: 3-amino-N-[(6S)-2-[(3R,4R)-3-amino-4-(difluoromethyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 346: 3-amino-N-[(6S)-2-[(3S,4S)-3-amino-4-(difluoromethyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 347: 3-amino-N-[(6S)-2-[(3R,4S)-3-amino-4-(difluoromethyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 354: 3-amino-N-[(6S)-2-[3,8-diazabicyclo[3.2.1]octan-3-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide; 363: 3-amino-N-[(6S)-2-[(3R,4S)-3-amino-4-(trifluoromethyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 364: 3-amino-N-[(6S)-2-[(3S,4R)-3-amino-4-(trifluoromethyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 376: 3-amino-N-[(6S)-2-[(3S,4R)-3-(difluoromethyl)-4-(methylamino)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 377: 3-amino-N-[(6S)-2-[(3R,4S)-3-(difluoromethyl)-4-(methylamino)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 384: 3-amino-N-[(6S)-2-[(3R,4S)-3-amino-4-(fluoromethyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 385: 3-amino-N-[(6S)-2-[(3S,4R)-3-amino-4-(fluoromethyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 427: 3-amino-N-[(6S)-2-[(3R,4S)-4-amino-3-methoxy-3-methylpyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 428: 3-amino-N-[(6S)-2-[(3S,4R)-4-amino-3-methoxy-3-methylpyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 430: 3-amino-N-[(6S)-2-[(5S,9R)-9-amino-2-oxa-7-azaspiro[4.4]nonan-7-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 431: 3-amino-N-[(6S)-2-[(5R,9S)-9-amino-2-oxa-7-azaspiro[4.4]nonan-7-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 437: 3-amino-N-[(6S)-2-[(5R,9R)-9-amino-2-oxa-7-azaspiro[4.4]nonan-7-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; 441: 3-amino-N-[(6S)-2-[(3R,4R)-3-(fluoromethyl)-4-(methylamino)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide; or 442: 3-amino-N-[(6S)-2-[(3S,4S)-3-(fluoromethyl)-4-(methylamino)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinolin-6-yl]-6-methylthieno[2,3-b]pyridine-2-carboxamide. 